US Liver Transplant Outcomes After Normothermic Regional Perfusion vs Standard Super Rapid Recovery.

Importance: Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). Objective: To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. Design, Setting, and Participants: This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. Exposures: cDCD livers were recovered by either NRP or SRR. Main Outcomes and Measures: The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. Results: A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. Conclusion and Relevance: There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

The American Society of Transplant Surgeons Consensus Statement on Normothermic Regional Perfusion.

On June 3, 2023, the American Society of Transplant Surgeons convened a meeting in San Diego, California to (1) develop a consensus statement with supporting data on the ethical tenets of thoracoabdominal normothermic regional perfusion (NRP) and abdominal NRP; (2) provide guidelines for the standards of practice that should govern thoracoabdominal NRP and abdominal NRP; and (3) develop and implement a central database for the collection of NRP donor and recipient data in the United States. National and international leaders in the fields of neuroscience, transplantation, critical care, NRP, Organ Procurement Organizations, transplant centers, and donor families participated. The conference was designed to focus on the controversial issues of neurological flow and function in donation after circulatory death donors during NRP and propose technical standards necessary to ensure that this procedure is performed safely and effectively. This article discusses major topics and conclusions addressed at the meeting.

Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

Infection with Two Multi-Drug-Resistant Organisms in Solid Organ Transplant Patients Is Associated with Increased Mortality and Prolonged Hospitalization.

Background: Solid organ transplant recipients have several risk factors for peri-operative multi-drug-resistant infection: their immune system is dampened as a result of critical illness and surgical stress that may be further impaired by induction immunotherapy and broad-spectrum antibiotic prophylaxis promotes selection for resistant pathogens. Infection with multi-drug-resistant organisms (MDRO) results in morbidity and mortality for solid organ transplant recipients. Patients and Methods: To assess in-hospital mortality and hospitalization duration associated with these infections, we analyzed cross-sectional, retrospective data from the 2016 Agency for Healthcare and Quality, Healthcare Cost and Utilization Project's National Inpatient Sample. Our analysis included 31,105 index admissions records for liver, kidney, heart, lung, and pancreas transplant recipients in the United States. Outcomes were assessed by multivariable regression analysis adjusting for covariables. Results: One percent (355/29,451) of patients with diagnosis of no MDRO infections died, 3% (40/1491) with diagnosis of one MDRO infection died, and 15% (25/166) with diagnosis of two MDRO infections died. Diagnosis of one MDRO infection was associated with a 20-day increase in hospitalization duration (95% confidence interval [CI], 17-22) but not increased odds of death (odds ratio [OR], 1.2; 95% CI, 0.5-2.5). Diagnosis of two MDRO infections was associated with an increased odds of death (OR, 9.6' 95% CI, 3.3-27.9) and a 41-day increase in hospitalization duration (95% CI, 34-49). Conclusions: Strategies to decrease peri-operative MDRO infection may improve survival and decrease duration of hospitalization for solid organ transplant patients.

Operative Technique of Donor Organ Procurement for En Bloc Heart-liver Transplantation.

Combined heart-liver transplant is an emerging option for patients with indications for heart transplantation and otherwise prohibitive hepatic dysfunction. Heart-liver transplantation is particularly relevant for patients with single ventricle physiology who often develop Fontan-associated liver disease and fibrosis. Although only performed at a limited number of centers, several approaches to combined heart-liver transplantation have been described. The en bloc technique offers several potential advantages over the traditional sequential technique. Specifically, en bloc heart-liver transplantation may allow improved hemodynamics, decreased bleeding, reduced liver allograft ischemic time, and may result in reduced rates of graft dysfunction. Here we describe our center's en bloc heart-liver procurement technique in detail, with the aim of allowing broader use and standardization of this technique.

What solid organ transplant healthcare providers should know about renin-angiotensin-aldosterone system inhibitors and COVID-19.

The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID-19) are still emerging. Kidney transplant recipients are commonly prescribed renin-angiotensin-aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin-converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS-CoV-2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID-19 pandemic. At present, there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID-19 pandemic.

Eliminating international normalized ratio threshold for transfusion in pediatric patients with acute liver failure.

INTRODUCTION: Transfusion protocols are not well-studied for pediatric patients with acute liver failure (ALF). This study evaluates the utility of an international normalized ratio (INR)-based transfusion threshold for these patients. METHODS: Forty-four ALF pediatric patients from 2009 to 2018 were reviewed and divided into two groups: (a) a threshold group including patients between 2009 and 2015 who were transfused for an INR above 3.0, per institutional policy (n = 30), and (b) a post-threshold group including patients after 2015 through 2018 who were transfused based on clinical judgment (n = 14). Preoperative INRs, preoperative transfusions, intraoperative transfusions, early reoperation, renal function, graft function and deaths were compared. RESULTS: Liver failure severity was similar between threshold and post-threshold groups. Threshold patients had a lower average INR prior to transplantation, 2.8 (range 1.8-3.8) vs 4.4 (range 2.1-9.0), respectively (P = .01). Twenty-six threshold patients (87%) received preoperative FFP compared with seven post-threshold patients (50%, P = .0088). Two threshold patients (7%) received preoperative cryoprecipitate compared with five post-threshold patients (36%, P = .014). The incidence of pre-transplant bleeding, operative transfusions, and 1-year patient and graft survival did not differ significantly. CONCLUSION: Clinical judgment vs an INR-based threshold for transfusions did not increase perioperative complications in children with ALF.

Ureterostomy as an alternative to ileal conduits in pediatric kidney transplantation.

INTRODUCTION: Urinary diversion in pediatric renal transplant candidates with bladders not amenable to primary reconstruction can be achieved by pre-transplant ileal conduit creation. We performed cutaneous ureterostomies to limit pre-transplant surgery, protect the peritoneum for dialysis, transplant patients sooner, and preserve ureter length for future surgical reconstruction. METHODS: We compared four pediatric transplant recipients with ureterostomies to four recipients with ileal conduits from 2009 to 2017. RESULTS: All patients with ileal conduits developed at least one urinary tract infection (UTI) within 1 year of transplant and three of four patients had recurrent UTIs within the first year. Two patients required ileal conduit revisions for redundant conduits and recurrent UTIs. Of the four ureterostomy patients, two patients had UTIs within one year of transplant. Two patients developed ureterostomy strictures requiring revision at the fascial level; one was associated with a UTI. CONCLUSION: In our small case series, ureterostomy allowed for a single operative intervention with preservation of ureter length for later reconstruction. Ureterostomy is safe and recurrent UTI may be lower in the ureterostomy group. Long-term evaluation of ureterostomy for urinary diversion in pediatric kidney transplant is warranted.

Superior Hypertension Management in Pediatric Kidney Transplant Patients After Native Nephrectomy.

BACKGROUND: Native nephrectomy in pediatric kidney transplant recipients is performed for multiple indications. Posttransplant hypertension requiring medical management is common, and the effect of native nephrectomy on posttransplant hypertension is poorly studied. Our aim is to evaluate the impact of native nephrectomy on posttransplant hypertension. METHODS: One hundred thirty-six consecutive pediatric kidney transplant recipients from 2007 to 2012 were studied at a single institution and divided into 2 groups: no nephrectomy and native nephrectomy (unilateral and bilateral nephrectomy). Antihypertensive medication use was evaluated before nephrectomy/transplant, at discharge from transplant and at 1, 3, and 5 years posttransplant. RESULTS: In a bivariate analysis, nephrectomy was associated with a significant reduction in the percentage of patients requiring antihypertensive medication at the time of discharge (27.3%) and 1 year posttransplant (10.7%) as compared with patients without nephrectomy (71.7%, and 50%, respectively, P < 0.05). This trend toward reduction in antihypertensive medication in the nephrectomy group as compared with the no nephrectomy group persisted at 3 (18.6% versus 43.2%) and 5 years (19.7% versus 37.5%) posttransplant. Multivariable logistic regression demonstrated that patients without native nephrectomy had higher odds of requiring antihypertensive medication at the time of discharge (3.3) and 1 year (5.2) as compared with patients who underwent native nephrectomy (P = 0.036 and P = 0.013, respectively). CONCLUSIONS: Native nephrectomy reduces the odds of needing antihypertensive medication after transplant. The impact of native nephrectomy is crucial to the comprehensive management of pediatric transplant recipients where medication compliance is challenging and lifelong hypertension is known to negatively impact cardiovascular health.

Experimental Approaches to Tissue Injury and Repair in Advanced Age.

Cutaneous wound healing is a complex physiological process. This process can be altered by multiple physiological and pathological factors. Multiple pathophysiological disturbances act to impair resolution of cutaneous wound injury, including obesity, diabetes, peripheral vascular disease, and advanced age. As our longevity increases without a concomitant increase in healthy living years, it is plausible to assume that problematic wound closure will continue to consume a large portion of our health care resources. Furthermore, advanced age is associated with numerous alterations in the innate and adaptive immune responses that complicate outcomes following cutaneous injury, trauma, or infection. Thus, models that examine the impact of advanced age on cutaneous wound repair will be of great benefit to the development of potential therapeutics that target age-related aberrancies in tissue repair. Herein, we detail two animal models of tissue injury, excisional wound injury and burn injury, that can be used to evaluate wound healing in the context of advanced age. We also describe modifications of these methods to examine wound infection following either excisional or burn injury. Lastly, we discuss methods of subsequent tissue analysis following injury. Models described below can be further adapted to genetically engineered murine strains to study the effects of aging and other co-morbidities on wound healing.

Episodic binge ethanol exposure impairs murine macrophage infiltration and delays wound closure by promoting defects in early innate immune responses.

BACKGROUND: Exacerbation of cutaneous wound infections and delayed wound closure are frequent complications seen in alcohol exposed subjects who sustain injuries. We previously reported that acute alcohol exposure alters the early dermal inflammatory phase of wound healing and also several parameters of the proliferative wound healing phase in wounds from ethanol (EtOH)-treated mice for several days or weeks after EtOH exposure. Hence, it is likely that the cumulative defects arising in the early phases of the wound healing process directly contribute to the increased complications observed in intoxicated patients at the time of injury. METHODS: C57BL/6 mice were given intraperitoneal EtOH (2.2 g/kg body weight) or vehicle (saline) EtOH using our episodic binge EtOH exposure protocol (3 days EtOH, 4 days off, 3 days EtOH) to yield a blood alcohol concentration (BAC) of 300 mg/dl at the time of wounding. Mice were subjected to six 3 mm full-thickness dorsal wounds and immediately treated topically with 10 µl of sterile saline (control) or diluted Staphylococcus aureus corresponding to 1 × 10(4) CFU/wound. Wounds were harvested at 24 hours post injury to evaluate wound area, neutrophil and macrophage accumulation, and the protein levels of cytokines, interleukin-6 (IL-6), IL-1ß, and IL-10, and chemokines, macrophage inflammatory protein-2 (MIP-2) and MIP-1α, monocyte chemotactic protein-1 (MCP-1), and keratinocyte-derived chemokine (KC). The abundance and localization of cathelicidin-related antimicrobial peptide (CRAMP) and the kallikrein epidermal proteases (KLK5 and KLK7) were also determined. RESULTS: Compared to control mice, EtOH-treated mice exhibited delayed wound closure, decreased macrophage accumulation, and impaired production of MIP-1α. Furthermore, skin from EtOH-treated mice demonstrated a reduction in the abundance of epidermal CRAMP and KLK7. CONCLUSIONS: These findings suggest that EtOH exposure hinders several distinct components of the innate immune response, including phagocyte recruitment and chemokine/cytokine and AMP production. Together, these effects likely contribute to delayed wound closure and enhanced infection severity observed in intoxicated patients.

The role of aryl hydrocarbon receptor in interleukin-23-dependent restoration of interleukin-22 following ethanol exposure and burn injury.

OBJECTIVE: T-helper (Th)-17 lymphocytes play a crucial role in maintenance and regulation of gut immunity. Our laboratory has demonstrated that acute ethanol (EtOH) exposure before burn injury results in intestinal T cell suppression and enhanced bacterial translocation. BACKGROUND: To extend these studies, we examined the effects of EtOH exposure and burn injury on Th17 responses within intestinal lymphoid Peyer's patches (PP). We further investigated whether restitution of interleukin (IL)-23 enhances PP cell IL-17 and IL-22 after EtOH and burn injury. METHODS: Male mice, approximately 25 g, were gavaged with EtOH (2.9 mg/kg) before receiving an approximately 12.5% total body surface area full thickness burn. One day postinjury, PP mixed cells were cultured in the presence of plate-bound anti-CD3/soluble anti-CD28 in the presence or absence of IL-23 for 48 hours. Supernatants were harvested for IL-17 and IL-22 levels. RESULTS: When combined with EtOH intoxication, burn injury significantly decreased IL-17 and IL-22, as compared with sham injury. IL-23 treatment successfully increased levels of IL-22 but not IL-17. This restoration was prevented when PP cells were treated with CH-223191, an aryl hydrocarbon receptor inhibitor. To further delineate the mechanism of differential IL-17 and IL-22 suppression, PP cells were treated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, which signal via protein kinase C (PKC) and calcium flux. Treatment with PMA and ionomycin significantly prevented the decrease in IL-17 but not IL-22 after EtOH exposure and burn injury. CONCLUSIONS: These findings suggest that IL-23-mediated restoration of IL-22 is aryl hydrocarbon receptor dependent, whereas IL-17 requires activation of protein kinase C and intracellular calcium signaling.

The aging lung.

There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction. Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older. With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.

G-CSF enhances resolution of Staphylococcus aureus wound infection in an age-dependent manner.

This study tested the hypothesis that heightened bacterial colonization and delayed wound closure in aged mice could be attenuated by granulocyte colony-stimulating factor (G-CSF) treatment. Previously, we reported that aged mice had elevated bacterial levels, protracted wound closure, and reduced wound neutrophil accumulation after Staphylococcus aureus wound infection relative to young mice. In aseptic wound models, G-CSF treatment improved wound closure in aged mice to rates observed in young mice. Given these data, our objective was to determine if G-CSF could restore age-associated differences in wound bacterial burden and closure by increasing wound neutrophil recruitment. Young (3- to 4-month) and aged (18- to 20-month) BALB/c mice received three dorsal subcutaneous injections of G-CSF (250 ng/50 µL per injection) or saline control (50 µL per injection) 30 min after wound infection. Mice were killed at days 3 and 7 after wound infection, and bacterial colonization, wound size, wound leukocyte accumulation, and peripheral blood were evaluated. At days 3 and 7 after wound infection, bacterial colonization was significantly reduced in G-CSF-treated aged mice to levels observed in saline-treated young animals. Wound size was reduced in G-CSF-treated aged animals, with no effect on wound size in G-CSF-treated young mice. Local G-CSF treatment significantly enhanced neutrophil wound accumulation in aged mice, whereas there was no G-CSF-induced change in young mice. These data demonstrate that G-CSF enhances bacterial clearance and wound closure in an age-dependent manner. Moreover, G-CSF may be of therapeutic potential in the setting of postoperative wound infection or chronic nonhealing wounds in elderly patients.

Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age.

Advanced age is associated with alterations in innate and adaptive immune responses, which contribute to an increased risk of infection in elderly patients. Coupled with this immune dysfunction, elderly patients demonstrate impaired wound healing with elevated rates of wound dehiscence and chronic wounds. To evaluate how advanced age alters the host immune response to cutaneous wound infection, we developed a murine model of cutaneous Staphylococcus aureus wound infection in young (3-4 mo) and aged (18-20 mo) BALB/c mice. Aged mice exhibit increased bacterial colonization and delayed wound closure over time compared with young mice. These differences were not attributed to alterations in wound neutrophil or macrophage TLR2 or FcγRIII expression, or age-related changes in phagocytic potential and bactericidal activity. To evaluate the role of chemotaxis in our model, we first examined in vivo chemotaxis in the absence of wound injury to KC, a neutrophil chemokine. In response to a s.c. injection of KC, aged mice recruited fewer neutrophils at increasing doses of KC compared with young mice. This paralleled our model of wound infection, where diminished neutrophil and macrophage recruitment was observed in aged mice relative to young mice despite equivalent levels of KC, MIP-2, and MCP-1 chemokine levels at the wound site. This reduced leukocyte accumulation was also associated with lower levels of ICAM-1 in wounds from aged mice at early time points. These age-mediated defects in early neutrophil recruitment may alter the dynamics of the inflammatory phase of wound healing, impacting macrophage recruitment, bacterial clearance, and wound closure.