Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need ...in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production.
To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant.
The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction;
<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days;
<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access.
Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.
Current treatment strategies for severe septic conditions (i.e., intravenous fluids, vasopressors, and cardiac inotropes) reestablish fluid balance and improve cardiac systole but do not address ...diastolic dysfunction. Our study aimed to fully characterize both systolic and diastolic abnormalities of sepsis-associated heart failure and to identify treatment that would support full-cycle cardiac improvement.
Endotoxin-injected rabbits, an animal model of abnormal cardiac function in human sepsis, were used to delineate cardiac abnormalities and to examine effects of drug treatments on heart systolic and diastolic function (n = 30); saline-injected animals served as comparators (n = 17). As treatment, three inotropes commonly used for treatment of cardiac failure were infused for 45 mins in separate animal groups-milrinone, dobutamine, and levosimendan.
Variables of left ventricular systolic and diastolic function were assessed with a pressure conductance catheter. Measurements were made before and after endotoxin/saline injection and before and after inotrope treatment.
Pressure-volume analyses of the left ventricle showed marked impairment in systolic function and in all indices of diastolic function (isovolumic relaxation time constant, left ventricular end-diastolic pressure, and end-diastolic pressure-volume relationship) in endotoxin-treated rabbits. The inotropes, milrinone, dobutamine, and levosimendan, could each partially or completely restore systolic function in the lipopolysaccharide-treated rabbits. However, only levosimendan therapy led to additional beneficial effects on left ventricular relaxation and diastolic function.
Cardiac failure in severe sepsis results from impairments in both systolic and diastolic functions. Treatment with the calcium sensitizer levosimendan improved both systolic and diastolic cardiac functions in septic animals, but cyclic adenosine monophosphate-dependent inotropes milrinone and dobutamine only improved systolic function.
Acute heart failure is a major health care problem and data on patient journey before/during/after hospitalization are limited. The aim of this study was to analyze patient journey from pre-hospital ...to discharge in acute heart failure in a multicentre observational study.
This observational study enrolled, one day per week, 257 patients with acute heart failure during five months (September 2014 – February 2015) in 14 departments of Paris (cardiology: 10; geriatrics: 4). Mean age was 77±15 years, 56% were male. First medical contact was an emergency department in 45% of cases, a general practitioner (GP) in 16%, and a cardiologist or a medical ambulance (13% each).
There was a single medical actor intervention before hospitalization in 78% of cases. 64% of patients were finally admitted through emergency departments. Previous history of heart failure was common (71%) and most frequent precipitating factors were arrhythmia (29%), infection (26%) and non-compliance to medical therapy (16%). Diabetes (28%), chronic pulmonary disease (19%) and cognitive disabilities (18%) were the most frequent co-morbidities. LVEF was preserved (>50%) in 32%. In-hospital stay was 13±12 days and 61% of patients stayed in an intensive cardiologic care unit (ICCU) for an average duration of 5.5±3.9 days. 64% of patients were directly discharged home and 21% were transferred to rehabilitation care units. In-hospital mortality was 2.4%.
Although heterogeneous patient admission for acute heart failure is made through emergency departments and GPs in the majority of cases, a stay in intensive care unit is observed in 61% of cases. Discharge from hospital is made at home in 2/3 of cases.
Therefore, actions to improve cooperation between professionals in the management of acute heart failure should target emergency departments and GPs. Display omitted
PDF
