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Cellular dynamics in pig-to-human kidney xenotransplantation

Pan, Wanqing; Zhang, Weimin; Zheng, Binghan; Camellato, Brendan R; Stern, Jeffrey; Lin, Ziyan; Khodadadi-Jamayran, Alireza; Kim, Jacqueline; Sommer, Philip; Khalil, Karen; Weldon, Elaina; Bai, Jiangshan; Zhu, Yinan; Meyn, Peter; Heguy, Adriana; Mangiola, Massimo; Griesemer, Adam; Keating, Brendan J; Montgomery, Robert A; Xia, Bo; Boeke, Jef D
BACKGROUND:Xenotransplantation of genetically engineered porcine organs has the potential to address the challenge of organ donor shortage. Two cases of porcine-to-human kidney xenotransplantation were performed, yet the physiological effects on the xenografts and the recipients' immune responses remain largely uncharacterized. METHODS:We performed single-cell RNA sequencing (scRNA-seq) and longitudinal RNA-seq analyses of the porcine kidneys to dissect xenotransplantation-associated cellular dynamics and xenograft-recipient interactions. We additionally performed longitudinal scRNA-seq of the peripheral blood mononuclear cells (PBMCs) to detect recipient immune responses across time. FINDINGS/RESULTS:Although no hyperacute rejection signals were detected, scRNA-seq analyses of the xenografts found evidence of endothelial cell and immune response activation, indicating early signs of antibody-mediated rejection. Tracing the cells' species origin, we found human immune cell infiltration in both xenografts. Human transcripts in the longitudinal bulk RNA-seq revealed that human immune cell infiltration and the activation of interferon-gamma-induced chemokine expression occurred by 12 and 48 h post-xenotransplantation, respectively. Concordantly, longitudinal scRNA-seq of PBMCs also revealed two phases of the recipients' immune responses at 12 and 48-53 h. Lastly, we observed global expression signatures of xenotransplantation-associated kidney tissue damage in the xenografts. Surprisingly, we detected a rapid increase of proliferative cells in both xenografts, indicating the activation of the porcine tissue repair program. CONCLUSIONS:Longitudinal and single-cell transcriptomic analyses of porcine kidneys and the recipient's PBMCs revealed time-resolved cellular dynamics of xenograft-recipient interactions during xenotransplantation. These cues can be leveraged for designing gene edits and immunosuppression regimens to optimize xenotransplantation outcomes. FUNDING/BACKGROUND:This work was supported by NIH RM1HG009491 and DP5OD033430.
PMID: 38776915
ISSN: 2666-6340
CID: 5654702

Limb Necrosis in the Setting of Vasopressor Use

Derry, Kendall H; Rocks, Madeline C; Izard, Paul; Nicholas, Rebecca S; Sommer, Philip M; Hacquebord, Jacques H
BACKGROUND:It remains poorly understood why only some hemodynamically unstable patients who receive aggressive treatment with vasopressor medications develop limb necrosis. OBJECTIVE:To determine the incidence of limb necrosis and the factors associated with it following high-dose vasopressor therapy. METHODS:A retrospective case-control medical records review was performed of patients aged 18 to 89 years who received vasopressor therapy between 2012 and 2021 in a single academic medical center. The study population was stratified by the development of limb necrosis following vasopressor use. Patients who experienced necrosis were compared with age- and sex-matched controls who did not experience necrosis. Demographic information, comorbidities, and medication details were recorded. RESULTS:The incidence of limb necrosis following vasopressor administration was 0.25%. Neither baseline demographics nor medical comorbidities differed significantly between groups. Necrosis was present in the same limb as the arterial catheter most often for femoral catheters. The vasopressor dose administered was significantly higher in the necrosis group than in the control group for ephedrine (P = .02) but not for the other agents. The duration of therapy was significantly longer in the necrosis group than in the control group for norepinephrine (P = .001), epinephrine (P = .04), and ephedrine (P = .01). The duration of vasopressin administration did not differ significantly between groups. CONCLUSION/CONCLUSIONS:The findings of this study suggest that medication-specific factors, rather than patient and disease characteristics, should guide clinical management of necrosis in the setting of vasopressor administration.
PMID: 38688844
ISSN: 1937-710x
CID: 5658052

The decedent model: A new paradigm for de-risking high stakes clinical trials like xenotransplantation

Montgomery, Robert A; Griesemer, Adam D; Segev, Dorry L; Sommer, Philip
The first 2 living recipients of pig hearts died unexpectedly within 2 months, despite both recipients receiving what over 30 years of nonhuman primate (NHP) research would suggest were the optimal gene edits and immunosuppression to ensure success. These results prompt us to question how faithfully data from the NHP model translate into human outcomes. Before attempting any further heart xenotransplants in living humans, it is highly advisable to gain a more comprehensive understanding of why the promising preclinical NHP data did not accurately predict outcomes in humans. It is also unlikely that additional NHP data will provide more information that would de-risk a xenoheart clinical trial because these cases were based on the best practices from the most successful NHP results to date. Although imperfect, the decedent model offers a complementary avenue to determine appropriate treatment regimens to control the human immune response to xenografts and better understand the biologic differences between humans and NHP that could lead to such starkly contrasting outcomes. Herein, we explore the potential benefits and drawbacks of the decedent model and contrast it to the advantages and disadvantages of the extensive body of data generated in the NHP xenoheart transplantation model.
PMID: 38341026
ISSN: 1600-6143
CID: 5635522

Single center utilization and post-transplant outcomes of thoracoabdominal normothermic regional perfusion deceased cardiac donor organs

Motter, Jennifer D; Jaffe, Ian S; Moazami, Nader; Smith, Deane E; Kon, Zachary N; Piper, Greta L; Sommer, Philip M; Reyentovich, Alex; Chang, Stephanie H; Aljabban, Imad; Montgomery, Robert A; Segev, Dorry L; Massie, Allan B; Lonze, Bonnie E
INTRODUCTION:Thoracoabdominal normothermic regional perfusion (TA-NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA-NRP-procured organs are limited by potential misclassification since TA-NRP is not differentiated from donation after cardiac death (DCD) in registry data. METHODS:We studied 22 donors whose designees consented to TA-NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022. We identified these donors in SRTR to describe organ utilization and recipient outcomes and compared them to recipients of traditional DCD (tDCD) and donation after brain death (DBD) organs during the same timeframe. RESULTS:All 22 donors progressed to cardiac arrest and underwent TA-NRP followed by heart, lung, kidney, and/or liver procurement. Median donor age was 41 years, 55% had anoxic brain injury, 45% were hypertensive, 0% were diabetic, and median kidney donor profile index was 40%. TA-NRP utilization was high across all organ types (88%-100%), with a higher percentage of kidneys procured via TA-NRP compared to tDCD (88% vs. 72%, p = .02). Recipient and graft survival ranged from 89% to 100% and were comparable to tDCD and DBD recipients (p ≥ .2). Delayed graft function was lower for kidneys procured from TA-NRP compared to tDCD donors (27% vs. 44%, p = .045). CONCLUSION:Procurement from TA-NRP donors yielded high organ utilization, with outcomes comparable to tDCD and DBD recipients across organ types. Further large-scale study of TA-NRP donors, facilitated by its capture in the national registry, will be critical to fully understand its impact as an organ procurement technique.
PMID: 38445531
ISSN: 1399-0012
CID: 5691982

Impact of oral vancomycin treatment duration on rate of Clostridioides difficile recurrence in patients requiring concurrent systemic antibiotics

Kwiatkowski, Diana; Marsh, Kassandra; Katz, Alyson; Papadopoulos, John; So, Jonathan; Major, Vincent J; Sommer, Philip M; Hochman, Sarah; Dubrovskaya, Yanina; Arnouk, Serena
BACKGROUND:infection (CDI) in patients requiring concomitant systemic antibiotics. OBJECTIVES/OBJECTIVE:To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence. METHODS:(VRE). RESULTS:= .083) were not significantly different between groups. Discontinuation of vancomycin prior to completion of antibiotics was an independent predictor of 8-week recurrence on multivariable logistic regression (OR, 4.8; 95% CI, 1.3-18.1). CONCLUSIONS:Oral vancomycin prescribing relative to the systemic antibiotic end date may affect CDI recurrence to a greater extent than total vancomycin duration alone. Further studies are needed to confirm these findings.
PMID: 38288606
ISSN: 1559-6834
CID: 5627432

Pig-to-human heart xenotransplantation in two recently deceased human recipients

Moazami, Nader; Stern, Jeffrey M; Khalil, Karen; Kim, Jacqueline I; Narula, Navneet; Mangiola, Massimo; Weldon, Elaina P; Kagermazova, Larisa; James, Les; Lawson, Nikki; Piper, Greta L; Sommer, Philip M; Reyentovich, Alex; Bamira, Daniel; Saraon, Tajinderpal; Kadosh, Bernard S; DiVita, Michael; Goldberg, Randal I; Hussain, Syed T; Chan, Justin; Ngai, Jennie; Jan, Thomas; Ali, Nicole M; Tatapudi, Vasishta S; Segev, Dorry L; Bisen, Shivani; Jaffe, Ian S; Piegari, Benjamin; Kowalski, Haley; Kokkinaki, Maria; Monahan, Jeffrey; Sorrells, Lori; Burdorf, Lars; Boeke, Jef D; Pass, Harvey; Goparaju, Chandra; Keating, Brendan; Ayares, David; Lorber, Marc; Griesemer, Adam; Mehta, Sapna A; Smith, Deane E; Montgomery, Robert A
Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.
PMID: 37488288
ISSN: 1546-170x
CID: 5595152

Mechanical circulatory support in the intensive care unit

Sommer, Philip; Nunnally, Mark
PMID: 35993668
ISSN: 1537-1913
CID: 5331492

Efficacy of Proning in Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation

Chang, Stephanie H; Smith, Deane E; Carillo, Julius A; Sommer, Philip M; Geraci, Travis C; Williams, David; Paone, Darien; Goldernberg, Ronald; Chan, Justin; Kon, Zachary N; Galloway, Aubrey C; Moazami, Nader
Objectives/UNASSIGNED:Proning patients with acute respiratory distress syndrome (ARDS) has been associated with increased survival, though little data exists evaluating the safety and feasibility of proning ARDS patients on extracorporeal membrane oxygenation (ECMO). Methods/UNASSIGNED:, 2020 was performed. All proning events were evaluated for complications, as well as change in compliance, sweep, oxygenation and flow. The primary outcome of this study was the rate major morbidity associated with proning while on ECMO. Results/UNASSIGNED:of 86 pre to 103 post (p<0.0001). Mean ECMO flow was unchanged. Conclusions/UNASSIGNED:Proning in patients with ARDS on ECMO is safe with an associated improvement in lung mechanics. With careful planning and coordination, these data support the practice of appropriately proning patients with severe ARDS, even if they are on ECMO.
PMCID:9499985
PMID: 36168330
ISSN: 2666-2507
CID: 5334262

Results of Two Cases of Pig-to-Human Kidney Xenotransplantation [Case Report]

Montgomery, Robert A; Stern, Jeffrey M; Lonze, Bonnie E; Tatapudi, Vasishta S; Mangiola, Massimo; Wu, Ming; Weldon, Elaina; Lawson, Nikki; Deterville, Cecilia; Dieter, Rebecca A; Sullivan, Brigitte; Boulton, Gabriella; Parent, Brendan; Piper, Greta; Sommer, Philip; Cawthon, Samantha; Duggan, Erin; Ayares, David; Dandro, Amy; Fazio-Kroll, Ana; Kokkinaki, Maria; Burdorf, Lars; Lorber, Marc; Boeke, Jef D; Pass, Harvey; Keating, Brendan; Griesemer, Adam; Ali, Nicole M; Mehta, Sapna A; Stewart, Zoe A
BACKGROUND:Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS:We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS:in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS:Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).
PMID: 35584156
ISSN: 1533-4406
CID: 5230812

Potential predictors of circuit exchange in COVID-19 patients receiving ECMO support [Meeting Abstract]

Shakoor, A; Chen, S; Hyde, J; Wu, B; Kon, Z; Sommer, P; Piper, G; Smith, D
INTRODUCTION: An extracorporeal membrane oxygenation (ECMO) circuit exchange is a commonly encountered procedure with potential for significant hemodynamic risks in patients with already compromised physiology. We aim to examine potential predictors and safety of circuit exchanges (CE) in COVID-19 patients receiving veno-venous (VV) ECMO support.
METHOD(S): This is a single-center, retrospective study of 29 patients with COVID-19 infection requiring VV ECMO support between March 2020 and April 2020. Pre- ECMO characteristics, complications, and blood product requirements were compared between patients with and without CE using independent two-sample Student's t-tests for continuous variables and chi-squared test for categorical variables.
RESULT(S): Overall survival to discharge was 97% (28/29). 13 patients did not require any CE and 16 patients required a total of 42 CEs. There was no difference in baseline characteristics, pre-ECMO ventilator settings, SOFA, or VIS scores between patients who required a circuit exchange versus those who did not. However, patients who required circuit exchanges had a higher lactate at time of cannulation (1.83 vs 1.32, p=0.011). The CE group had a longer duration of ECMO support (53.31 vs 13.31 days, p=0.004), higher pulmonary complications defined as hemothorax or pneumothorax (8/16 vs 0/13, p=0.003), and higher blood product transfusions including packed red blood cell (5,525 mL vs 1,261 mL, p=0.0001), cryoprecipitate (1,735 mL vs 501 mL, p=0.004), and platelet (486 mL vs 111 mL, p=0.019). In the 42 CEs, no major complications, including hemodynamic instability or cardiac arrest, occurred during the exchange.
CONCLUSION(S): Severity of underlying lung injury, ECMO duration, and pre-cannulation lactate may be markers for potential CE in COVID-19 patients requiring ECMO. They may be associated with higher blood product transfusion requirements and while CEs are procedures performed in hemodynamically tenuous patients, they are able to be performed safely
EMBASE:637190514
ISSN: 1530-0293
CID: 5158282