Renal transplant waiting list mortality in COVID era: is it advisable to halt transplant activity?

INTRODUCTION: Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD). Since March 2020, transplant activity in Mexico has been affected due to the COVID-19 pandemic. OBJECTIVE: The aim of the study was to determine the impact on mortality of patients on the waiting list (WL) for cadaveric donor kidney transplantation in a referral hospital in Yucatán, due to suspension of activities due to the pandemic. MATERIAL AND METHODS: Patients over 18 years of age on the waiting list for kidney transplantation at this hospital. In the event of a patient's death, the cause was investigated, especially if it was associated with COVID-19. A two-tailed p ≤ 0.05 was considered significant in all analyzes. RESULTS: The odds ratio (OR) of death from COVID-19 in a patient with ESRD in the WL in 2020 was OR = 5.04 (95% CI: 1.65-7.14, p = 0.023). The OR of dying with ESRD in the WL with a delay in the follow-up visits was OR = 6.59 (95% CI: 2.7-16.28, p = 0.008). CONCLUSION: The probability of death of a patient with ESRD with delayed follow-up visits and transplant retention is statistically higher than the probability of death from COVID-19.

INTRODUCCIÓN: El trasplante renal es el tratamiento de elección de la enfermedad renal en etapa terminal (ERT). Desde marzo de 2020, la actividad de trasplantes en México se ha visto afectada debido a la pandemia de COVID-19. OBJETIVO: Determinar el impacto en la mortalidad de pacientes en lista de espera (LE) para trasplante renal de donante cadavérico en un hospital de referencia en Yucatán, por suspensión de actividades debido a la pandemia. MATERIAL Y MÉTODOS: Pacientes > 18 años en LE para trasplante renal en este hospital. En caso de muerte de un paciente, se investigó la causa, especialmente si estaba asociada a COVID-19. Un valor de p de dos colas ≤ 0.05 se consideró significativo en todos los análisis. RESULTADOS: La razón de probabilidad de muerte por COVID-19 en un paciente con ERT en la LE en 2020 fue OR = 5.04 (IC 95%: 1.65-7.14, p = 0.023). La razón de probabilidad de morir con ERT en la LE con retraso en las consultas de seguimiento fue de OR = 6.59 (IC 95%: 2.7-16.28, p = 0.008). CONCLUSIÓN: La probabilidad de muerte de un paciente con ERT en la LE con retraso en las consultas de seguimiento y retención del trasplante es estadísticamente más alta que la probabilidad de muerte por COVID-19.

How to Handle Arterial Conduits in Liver Transplantation? Evidence From the First Multicenter Risk Analysis.

OBJECTIVE: The aims of the present study were to identify independent risk factors for conduit occlusion, compare outcomes of different AC placement sites, and investigate whether postoperative platelet antiaggregation is protective. BACKGROUND: Arterial conduits (AC) in liver transplantation (LT) offer an effective rescue option when regular arterial graft revascularization is not feasible. However, the role of the conduit placement site and postoperative antiaggregation is insufficiently answered in the literature. STUDY DESIGN: This is an international, multicenter cohort study of adult deceased donor LT requiring AC. The study included 14 LT centers and covered the period from January 2007 to December 2016. Primary endpoint was arterial occlusion/patency. Secondary endpoints included intra- and perioperative outcomes and graft and patient survival. RESULTS: The cohort was composed of 565 LT. Infrarenal aortic placement was performed in 77% of ACs whereas supraceliac placement in 20%. Early occlusion (≤30 days) occurred in 8% of cases. Primary patency was equivalent for supraceliac, infrarenal, and iliac conduits. Multivariate analysis identified donor age >40 years, coronary artery bypass, and no aspirin after LT as independent risk factors for early occlusion. Postoperative antiaggregation regimen differed among centers and was given in 49% of cases. Graft survival was significantly superior for patients receiving aggregation inhibitors after LT. CONCLUSION: When AC is required for rescue graft revascularization, the conduit placement site seems to be negligible and should follow the surgeon's preference. In this high-risk group, the study supports the concept of postoperative antiaggregation in LT requiring AC.

Subnormothermic Oxygenated Perfusion Optimally Preserves Donor Kidneys Ex Vivo.

INTRODUCTION: The current methods of preserving donor kidneys in nonoxygenated cold conditions minimally protect the kidney against ischemia-reperfusion injury (IRI), a major source of complications in clinical transplantation. However, preserving kidneys with oxygenated perfusion is not currently feasible due to the lack of an ideal perfusion mechanism that facilitates perfusion with blood at warm temperature. Here, we have designed an innovative renal pump circuit system that can perfuse blood or acellular oxygen carrier under flexible temperatures, pressures, and oxygenation. We have tested this apparatus to study optimal conditions of storage of our porcine model of donation after cardiac death (DCD) kidneys. METHODS: Porcine kidneys were retrieved after 30 minutes of cross-clamping renal pedicles in situ. Cessation of blood mimics postcardiac death in humans and simulates DCD warm ischemic injury. Procured kidneys were flushed and subjected to static cold storage (SCS) for 4 hours. For warm perfusion, kidneys were cannulated for pulsatile oxygenated perfusion with blood:PlasmaLyte for 4 hours at 15 °C, 22 °C, and 37 °C. To mimic posttransplant scenario, all kidneys were reperfused with blood for an additional 4 hours at 37 °C. RESULTS: Compared with all other groups, 22 °C perfusion resulted in significant reduction of acute tubular necrosis (ATN), apoptosis, kidney damage markers, Toll-like receptor signaling, and cytokine production. It was associated with maximal renal blood flow and urine output. Kidneys stored at 15 °C thrombosed within 2 hours under this condition. Martius Scarlet Blue staining confirmed that 22 °C was the optimal temperature to minimize hemorrhage and blood clots. CONCLUSION: Our novel study shows that oxygenated perfusion at near-room-temperature provides optimal donor kidney storage conditions.

Bidirectional graft-host hematological traffic in liver transplantation.

The highly complex immuno-hematological system of the recipient has to rebalance itself when the liver is replaced with a graft that has its own system. This gives us an opportunity for observation. Here we consider the graft-to-recipient direction with passenger lymphocyte syndrome (PLS) as well as the recipient-to-graft direction with Factor VIII (FVIII) inhibitors, paroxysmal nocturnal hemoglobinuria (PNH) and graft endothelial replacement with liver transplantation. PLS extends beyond the ABO blood groups to any situation where the donor has been sensitized to a recipient antigen. PLS directed against ABO or minor blood group antigens is usually self limiting whereas Rhesus (Rh) PLS persists with life threatening immune hemolysis. Human platelet antigen (HPA) 1A PLS results in life threatening immune thrombocytopenia. Treatments of severe PLS may include reduction in immunosuppression, anti-B-cell therapy, plasmapheresis and splenectomy. Liver transplantation into recipients with FVIII inhibitors has been difficult. Donors with acquired hemophilia may transmit the capacity to make FVIII inhibitors by PLS and should be avoided. Patients with PNH have been transplanted successfully but a considerable cost in the continued use of high dose eculizumab. We speculate that combined bone marrow and liver transplantation would be a better option for recipients with FVIII inhibitors or PNH. Replacement of liver graft endothelium with recipient cells is common and may explain relative transplant tolerance that is believed to occur with liver transplantation.

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε+Vα7.2+CD161++ or CD3ε+MR1 tetramer+ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression.

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vß-specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses.

Management of colorectal cancer with synchronous liver metastases: impact of multidisciplinary case conference review.

BACKGROUND: While no evidence exists to support mandatory multidisciplinary case conference (MCC) review for patients with synchronous colorectal cancer and liver metastases, this unique population may benefit greatly from multidisciplinary discussion. METHODS: We retrospectively identified patients who underwent liver resection with curative intent for colorectal liver metastases (CRLM) at a tertiary center between January 2008 and June 2015. The characteristics of patients discussed at a weekly regional MCC were examined, and the effect of MCC review on treatment approach was assessed. RESULTS: Sixty-six patients underwent elective surgery for synchronous colorectal cancer and liver metastases during the study period. Twenty-nine patients (44%) were presented at a MCC. Presentation was associated with greater likelihood of undergoing simultaneous or liver-first resection (P≤0.0001), with no difference in the extent of liver resection or location of primary tumor between the groups. A greater proportion of patients received chemotherapy and/or radiation following MCC discussion, without statistical significance. CONCLUSIONS: The treatment approach for patients with synchronous colorectal cancer and liver metastases may be significantly altered based on MCC review. Multidisciplinary discussion is advocated in order to facilitate equal access to individualized care.