Residual endotoxin induces primary graft dysfunction through ischemia/reperfusion-primed alveolar macrophages.

Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.

Increased Intraoperative Fluid Administration Is Associated with Severe Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: Severe primary graft dysfunction (PGD) is a major cause of early morbidity and mortality in patients after lung transplantation. The etiology and pathophysiology of PGD is not fully characterized and whether intraoperative fluid administration increases the risk for PGD remains unclear from previous studies. Therefore, we tested the hypothesis that increased total intraoperative fluid volume during lung transplantation is associated with the development of grade-3 PGD. METHODS: This retrospective cohort analysis included patients who had lung transplantation at the Cleveland Clinic between January 2009 and June 2013. We used multivariable logistic regression with adjustment for donor, recipient, and perioperative confounding factors to examine the association between total intraoperative fluid administration and development of grade-3 PGD in the initial 72 postoperative hours. Secondary outcomes included time to initial extubation and intensive care unit length of stay. RESULTS: Grade-3 PGD occurred in 123 of 494 patients (25%) who had lung transplantation. Patients with grade-3 PGD received a larger volume of intraoperative fluid (median 5.0 [3.8, 7.5] L) than those without grade-3 PGD (3.9 [2.8, 5.2] L). Each intraoperative liter of fluid increased the odds of grade-3 PGD by approximately 22% (adjusted odds ratio, 1.22; 95% confidence interval [CI], 1.12-1.34; P <0.001). The volume of transfused red blood cell concentrate was associated with grade-3 PGD (1.1 [0.0, 1.8] L for PGD-3 vs 0.4 [0.0, 1.1 for nongrade-3 PGD] L; adjusted odds ratio, 1.7; 95% CI, 1.08-2.7; P = 0.002). Increased fluid administration was associated with longer intensive care unit stay (adjusted hazard ratio, 0.92; 97.5% CI, 0.88-0.97; P < 0.001) but not with time to initial tracheal extubation (hazard ratio, 0.97; 97.5% CI, 0.93-1.02; P = 0.17). CONCLUSIONS: Increased intraoperative fluid volume is associated with the most severe form of PGD after lung transplant surgery. Limiting fluid administration may reduce the risk for development of grade-3 PGD and thus improve early postoperative morbidity and mortality after lung transplantation.

Intraoperative use of several inotropes is associated with increased mid-term mortality in patients undergoing orthotopic heart transplantation.

INTRODUCTION: Orthotopic heart transplantation (OHT) is the gold standard treatment for patients with end-stage heart failure. Inotropic agents are the hemodynamic mainstay in the treatment of implanted donor hearts. However, their infusion, particularly in excess, can have unintended consequences that lead to cardiac toxicity and can originate malignant arrhythmias, myocardial necrosis, and myocyte apoptosis. OBJECTIVE: The aim of the study was to determine the perioperative predictors of mid-term mortality after OHT. METHODS: We retrospectively studied all consecutive adult patients who underwent OHT between January 2009 and July 2013 at a tertiary care university hospital and followed them up until July 2013. Donor and recipient demographic data, hemodynamic profile, and perioperative data were analyzed. The primary endpoint was mid-term survival. RESULTS: The overall survival rate was 80.6% during hospitalization time and 70.1% after 328 (interquartile range, 643) days of follow-up. The univariate analysis showed that patients who died were older, had lower height and body surface area, donor/recipient (D/R) mismatch, prior cardiac surgery, longer cardiopulmonary bypass (CPB) time, postoperative lower left ventricular ejection fraction, sepsis, and primary graft dysfunction. Using Cox survival analysis, the independent risk factors related to mid-term mortality were intraoperative use of more than 2 inotropic drugs (hazard ratio [HR], 3.887; 95% confidence interval [CI], 1.224-12.342; P = .021), CPB duration (HR, 1.008; 95% CI, 1.003-1.014; P = .002), and D/R weight ratio (HR, 1.027; 95% CI, 1.009-1.046; P = .003). CONCLUSION: In patients undergoing OHT, mid-term survival was mostly related to D/R weight mismatch and intraoperative factors, mainly inotropic drugs and CPB duration.

Brilliant blue FCF as an alternative dye for saphenous vein graft marking: effect on conduit function.

IMPORTANCE: Surgical skin markers are used off-label to mark human saphenous veins (HSVs) to maintain orientation before implantation as aortocoronary or peripheral arterial bypass grafts. These surgical skin markers impair functional responses of the HSV tissue. OBJECTIVES: To investigate the effect of brilliant blue dye 1 (brilliant blue FCF [for food coloring]; hereinafter, FCF) as a nontoxic alternative marking dye and to determine whether FCF has pharmacological properties. DESIGN, SETTING, AND PARTICIPANTS: Segments of HSVs were collected in university hospitals from patients undergoing coronary artery bypass grafting procedures immediately after harvest (unmanipulated) or after typical intraoperative surgical graft preparation (after manipulation). Rat inferior venae cavae were used to determine the pharmacological properties and cellular targets of FCF. Endothelial and smooth muscle functional responses were determined in a muscle bath, and intimal thickening in HSVs was determined after 14 days in organ culture. MAIN OUTCOMES AND MEASURES: Contractile responses were measured in force and converted to stress. Smooth muscle function was expressed as maximal responses to potassium chloride depolarization contractions. Endothelial function was defined as the percentage of relaxation of maximal agonist-induced contraction. Neointimal thickness was measured by histomorphometric analysis. RESULTS: Human saphenous veins stored in the presence of FCF had no loss of endothelial or smooth muscle function. Unmanipulated HSVs preserved in the presence of FCF demonstrated a significant increase in endothelial-dependent relaxation (mean [SEM], 25.2% [6.4%] vs 30.2% [6.7%]; P = .02). Application of FCF to functionally nonviable tissue significantly enhanced the smooth muscle responses (mean [SEM], 0.018 [0.004] × 105 N/m² vs 0.057 [0.016] × 105 N/m²; P = .05). Treatment with FCF reduced intimal thickness in organ culture (mean [SEM], -17.5% [2.1%] for unmanipulated HSVs vs -27.9% [3.7%] for HSVs after manipulation; P < .001). In rat inferior venae cavae, FCF inhibited the contraction induced by the P2X7 receptor agonist 2'(3')-O-(4-benzoyl)benzoyl-adenosine-5'-triphosphate (mean [SEM], 14.8% [2.2%] vs 6.5% [1.8%]; P = .02) to an extent similar to the P2X7 receptor antagonist oxidized adenosine triphosphate (mean [SEM], 5.0% [0.9%]; P < .02 vs control) or the pannexin hemichannel inhibitor probenecid (mean [SEM], 7.3% [1.6%] and 4.7% [0.9%] for 0.5mM and 2mM, respectively; P < .05). CONCLUSIONS AND RELEVANCE: Treatment with FCF did not impair endothelial or smooth muscle function in HSVs. Brilliant blue FCF enhanced endothelial-dependent relaxation, restored smooth muscle function, and prevented intimal hyperplasia in HSVs in organ culture. These pharmacological properties of FCF may be due to P2X7 receptor or pannexin channel inhibition. Brilliant blue FCF is an alternative, nontoxic marking dye that may improve HSV conduit function and decrease intimal hyperplasia.

Estudio retrospectivo comparativo entre sevoflurano y propofol en el mantenimiento de la anestesia durante el trasplante hepático. Efectos sobre la función renal y hepática / Retrospective comparative study between sevoflurane and propofol in maintaining anaesthesia during liver transplant: effects on kidney and liver function

Objetivo. Comparar la repercusión postoperatoria sobre la función hepática y renal del sevofluorano frente al propofol durante el mantenimiento de la anestesia en el trasplante hepático ortotópico, así como analizar la supervivencia a corto plazo en relación a dichas funciones. Pacientes y métodos. Análisis retrospectivo de pacientes sometidos a THO entre enero de 2002 y diciembre de 2009. Fueron excluidos los pacientes con hemodiálisis pretrasplante, los retrasplantes y trasplantes hepatorrenales. Se comparó la incidencia de insuficiencia renal aguda, disfunción inicial del injerto, síndrome de reperfusión, rechazo y el pico máximo de transaminasas en función del hipnótico utilizado. Resultados. Un 31,2% de los pacientes desarrolló insuficiencia renal aguda y un 11,9% disfunción inicial, sin diferencias entre los grupos. Hubo tendencia a una menor incidencia de disfunción inicial del injerto en el grupo sevoflurano (8,6 frente a 12,8%), menor pico de transaminasas (más de 2.000 U/L, 12,1 frente a 15,9%) y menor incidencia de síndrome de reperfusión (10,3 frente a 21,6%). Conclusiones. A pesar de que en el trasplante el metabolismo renal del sevofluorano está aumentado, no hemos encontrado mayor incidencia de insuficiencia renal aguda. El sevofluorano en la anestesia del trasplante de hígado es al menos igual de seguro sobre la función renal y la función hepática que el propofol. Son necesarios nuevos trabajos prospectivos para clarificar la posible repercusión del hipnótico en el trasplante de hígado(AU)

Objective. To compare the post-operative effects of sevoflurane versus propofol on liver and kidney function while maintaining anaesthesia in the orthotopic liver transplant (OLT), as well as to analyse the short-term survival as regards these functions. Patients and methods. A retrospective analysis was conducted on patients subjected to an OLT between January 2002 and December 2009. Patients on pre-transplant haemodialysis, re-transplants, and hepatorenal transplants were excluded. The incidence of acute renal failure, initial dysfunction of the graft, reperfusion syndrome, rejection, and the transaminase peak depending value depending on the hypnotic used, were recorded. Results. About one-third (31.2%) of the patients developed acute renal failure and 11.9% an initial dysfunction, with no differences between the groups. There was a tendency for a lower incidence of initial dysfunction of the graft in the sevoflurane group (8.6% compared to 12.8%), a lower transaminase peak (greater than 2000 U/L, 12.1% versus 15.9%), and a lower incidence of reperfusion syndrome (10.3% compared to 21.6%). Conclusions. Despite the fact that the renal metabolism sevoflurane is elevated, we did not find any higher incidence of acute renal failure. Sevoflurane in the liver transplant anaesthesia is as least equally as safe propofol as regards renal function and liver function. New prospective studies are needed to clarify the possible effects of the hypnotic in liver transplant(AU)

Impaired kidney allograft function following ezetimibe therapy.

Although ezetimibe therapy has been shown to be effective in lowering serum cholesterol level, it has not been reported to affect serum cyclosporine level in transplant recipients. Here, we describe a kidney transplant recipient who experienced acute kidney allograft dysfunction after ezetimibe prescription. Our patient showed an increase in serum creatinine level as well as a decrease in serum cyclosporine levels 1 month after taking ezetimibe. This suggests that ezetimibe may interact with cyclosporine and decrease its serum level resulting in allograft dysfunction. In this regard, careful monitoring of kidney function along with the serum cyclosporine level in kidney allograft recipients is recommended when cyclosporine is co-administered with ezetimibe.

Fumarate in the preservation solution aggravates chronic allograft nephropathy.

Data on a protective role of fumarate in acute ischemia of the rat heart led to the obvious hypothesis that addition of fumarate to the preservation solution for kidney transplantation may have beneficial value. This study was designed to test this hypothesis. Kidneys of Lewis or Fischer 344 rats were flushed with University of Wisconsin (UW) solution or UW solution containing 5 mM fumarate. Grafts were immediately transplanted to Lewis recipients or stored at 4 °C for 5 h before transplantation. Renal function was assessed on d 10 and monthly for 6 mo. One group of isografts was removed on d 10 post-transplantation, the other groups of isografts and allografts after 6 mo. We detected a modest protective effect regarding proteinuria 10 d after isogeneic transplantation, and exclude the possibility that fumarate exerts acute nephrotoxicity. Surprisingly, fumarate strongly promoted intimal hyperplasia of allograft arteries, thickening of the arterial media of isografts and allografts, tubulo-interstitial allograft damage, and allograft infiltration by macrophages on the long run. To date, we do not know the mechanism resulting in fumarate-induced chronic graft damage. We suggest, however, that addition of fumarate to the conservation fluid does not improve graft outcome.

Aprotinin in lung transplantation is associated with an increased incidence of primary graft dysfunction.

OBJECTIVE: Aprotinin has been widely used to reduce bleeding and transfusion requirements in cardiac surgery and in lung transplantation. A recent study found a significant reduction in severe (grade III) primary graft dysfunction (PGD) in lung transplantation where aprotinin had been used. However, recently, concerns regarding the safety of aprotinin have been raised, and the future use of aprotinin is uncertain. In our institution, aprotinin has been widely used in cardiac surgery and transplantation. We decided to review our lung transplant caseload to investigate the impact of aprotinin on PGD and mortality and to guide our future clinical use of this antifibrinolytic. METHODS: A retrospective review of prospectively collected data on 213 consecutive patients who underwent single- or double-lung transplantation was performed. Ninety-nine patients, who received aprotinin, were compared with 114 patients who did not. The main outcome variables analysed were development of primary graft dysfunction, renal impairment and mortality. RESULTS: Aprotinin was associated with a significantly increased risk of PGD in the first 48 h postoperatively (p=0.01). CONCLUSIONS: In conclusion, although the benefits of aprotinin on blood loss are well established, this study does not provide support for the use of aprotinin to reduce PGD in lung transplantation and indicates that aprotinin may in fact have a detrimental effect.

[Immunosuppressive strategies and chronic graft dysfunction in kidney transplantation]. / Stratégies immunosuppressives et dysfonction chronique du greffon en transplantation rénale.

Chronic graft dysfunction is a major cause of return to dialysis. In the majority of cases, it is correlated with histological signs of cellular and/or humoral rejection, the nephrotoxicity of anticalcineurins, or nonspecific lesions of interstitial fibrosis and tubular atrophy. Although the incidence of acute rejection has considerably decreased, renal toxicity of the calcineurin inhibitors remains problematic. In cases of established nephrotoxicity, the use of non-nephrotoxic immunosuppressors such as mycophenolic acid or the proliferation signal inhibitors makes it possible to reduce or even stop the anticalcineurins. In prevention of anticalcineurin nephrotoxicity, many attempts to minimize or wean patients from them have shown that improvement in renal function is only obtained at the cost of an increase in the incidence of acute rejection. This makes it necessary to select patients who may benefit from anticalcineurin-sparing treatment, based on clinical, histological, and biological markers. Finally, long-term follow-up is also fundamental in order to validate the positive impact on renal function of this strategy in terms of graft survival.