31P MRS of heart grafts provides metabolic markers of early dysfunction

OBJECTIVE: Early graft failure (EGF) is a life-threatening event still accounting for a significant percentage of early deaths after heart transplantation. We tested whether selected metabolic markers, including high-energy phosphate concentrations measured ex vivo in pre-transplant heart grafts by (31)P magnetic resonance spectroscopy (MRS) are related with early post-transplant outcome. METHODS: During a 3-year period, 26 heart grafts harvested in the vicinity of the transplantation centre were studied. Evaluation of transplantability was done conventionally. (31)P MRS was performed ex vivo approximately 60min after aortic cross-clamp to quantify ATP, P(i) and PCr concentration ratios. A MRS-score was defined as a combination of intracellular pH (pHi) and the PCr/P(i) ratio. EGF was defined as the need to abnormally extend circulatory support or to use more than two inotropes before weaning the patient from CPB after transplantation. The grafts were attributed to three groups as follows: A1, transplanted with uneventful outcome (n=14); A2, transplanted with subsequent EGF (n=3) and B, not suitable for transplantation (n=9). RESULTS: Significant differences between groups existed for the following metabolic markers: PCr/ATP (P=0.013), PCr/P(i) (P=0.0004), pHi (P=0.0016) and MRS-score (P=0.0001). The sensitivity, specificity and positive likelihood ratio for EGF with a MRS-score\textlessor=1.95 were, respectively, 100%, 86% and 7. CONCLUSIONS: In the setting of this study, post-transplant outcome was related to the pre-transplant MRS-score of grafts evaluated ex vivo. This result might help to more securely use grafts from marginal donors

Role of endogenous adenosine as a predictive marker of vasoplegia during cardiopulmonary bypass and postoperative severe systemic inflammatory response.

OBJECTIVE: Systemic inflammatory response (SIRS) and severe SIRS (SIRS with organ dysfunction) occurring after cardiopulmonary bypass (CPB) are common causes of morbidity and mortality among cardiac surgical patients. These syndromes are often preceded by a profound vasodilation, characterized by vasoplegia occurring during surgery. Many substances have been implicated in their pathophysiology. Adenosine is a strong endogenous vasodilating agent released by endothelial cells and myocytes under metabolic stress and may be involved in blood pressure failure during CPB induced by severe SIRS. DESIGN: A prospective comparative observational study. SETTING: The operating room and intensive care unit of a tertiary care university hospital. PATIENTS: Adenosine plasma levels (mean+/-sd; APLs) were measured before (baseline), during, and immediately after surgery in 35 patients who underwent aortic valve replacement involving CPB. APLs were correlated to operative and postoperative clinical courses. MEASUREMENTS AND MAIN RESULTS: APLs were significantly higher in seven patients with vasoplegia and postoperative severe SIRS (1.6 micromol.L [0.2-2.6] vs. 0.4 micromol.L [0.1-1.0]) at baseline and during surgery. The duration of mechanical ventilation and stay in the intensive care unit were significantly longer for patients with higher APLs. Mean arterial pressure was inversely correlated with mean arterial APLs (Pearson's correlation coefficient: R=-0.66; p<.001). CONCLUSIONS: High APLs were found in patients with operative vasoplegia and postoperative severe SIRS occurring after cardiopulmonary bypass. This suggests that adenosine release is involved in vasoplegia that occurs during the systemic inflammatory response to cardiac surgery. Further studies are needed to clarify the association between cytokine production and adenosine release in severe SIRS following cardiac surgery

Severe right ventricular dysfunction is an independent predictor of pre- and post-transplant mortality among candidates for heart transplantation

International audienceBackground. Heart transplantation is the gold-standard treatment for end-stage heart failure. However, the shortage of grafts has led to longer waiting times and increased mortality for candidates without priority. Aims. To study waiting-list and post-transplant mortality, and their risk factors among patients registered for heart transplantation without initial high emergency procedure. Methods. All patients registered on the heart transplantation waiting list (2004-2015) without initial high emergency procedure were included. Clinical, biological, echocardiographic and haemodynamic data were collected. Waiting list and 1-year post-transplant survival were analysed with a Kaplan-Meier model. Results. Of 221 patients enrolled, 168 (76.0%) were men. Mean age was 50.0 +/- 12.0 years. Forty-seven patients died on the waiting list, resulting in mortality rates of 11.2 +/- 2.7% at 1 year, 31.9 +/- 5.4% at 2 years and 49.4 +/- 7.1% at 3 years. Median survival was 36.0 +/- 4.6 months. In the multivariable analysis, left ventricular ejection fraction 50 years were strong predictors of death after transplantation (HR: 5.38, 95% CI: 1.38-10.24 [P=0.020] and HR: 6.16, 95% CI: 1.62-9.32 [P=0.0130], respectively). Conclusions. Mortality among candidates for heart transplantation remains high. Patients at highest risk of waiting-list mortality have to be promoted, but without compromising post transplant outcomes. For this reason, candidates with severe right ventricular dysfunction are of concern, because, for them, transplantation is hazardous. (C) 2016 Elsevier Masson SAS. All rights reserved

Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling

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CD16/FC gamma R PROFILING ALLOWS NON INVASIVE APPRAISAL OF ANTIBODY-DEPENDENT NK CELL ALLOREACTIVE POTENTIAL IN HEART AND KIDNEY TRANSPLANT RECIPIENTS

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Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling

In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD

Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling

In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD

NATURAL KILLER CELL ACTIVATION IS A POTENT CYTOTOXIC MECHANISM SUSTAINING ADVERSE CYTOTOXIC EFFECTS OF DONOR-SPECIFIC ANTIBODIES IN SOLID ORGAN TRANSPLANTATION

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