The use of recombinant human activated protein C (drotrecogin alpha) in solid organ transplant recipients: case series and review of the literature.

Septic shock occurs frequently in solid organ transplant (SOT) recipients. Standard therapy includes fluid resuscitation, the administration of antimicrobials, and source control of the infection. Adjunctive therapy with recombinant human activated protein C (rhaPC), also called drotrecogin alpha, is another treatment that is used in patients but has not been studied in SOT patients. Concerns regarding the use of this drug in this patient population include the risk of bleeding and the potential to adversely affect graft survival. Here we report the largest case series of SOT recipients with septic shock who received rhaPC. This was a retrospective chart review that looked at the impact of this drug in the SOT population. In this single-center study, we identified 17 patients with a SOT and septic shock who received rhaPC. Six of the patients underwent kidney transplants, 5 received lung transplants, 4 received cadaveric liver transplants, and 2 received combined kidney/pancreas transplants. The average APACHE II score was 26.6 ± 5.5; all patients were undergoing mechanical ventilation and receiving vasopressors at the time of rhaPC administration. Overall mortality in the group was 23.5% (4/17) at 28 days post infusion. All of the deaths were due to complications of septic shock. Allograft survival was present in 13/17 (76.5%) of the patients at 28 days. Bleeding occurred in 17.6% of patients (3/17). The use of rhaPC appears to be associated with a favorable effect on mortality, with the potential for increased risk of bleeding. Clinicians must balance this risk with the potential benefit of this drug until further research can be conducted.

Fungal and mycobacterial infections after Campath (alemtuzumab) induction for renal transplantation.

OBJECTIVES: To report our experience with fungal and mycobacterial (tuberculosis) infection following induction with Campath (alemtuzumab). METHODS: We reviewed the database of 477 renal transplant patients induced with alemtuzumab. All those who had a fungal or mycobacterial infection were found, and the details of these complications reviewed. RESULTS: Five patients were found to have fungal (3) or tuberculous (2) infection. The incidence of fungal infection was 0.6% and that of tuberculous infection was 0.4%. Mortality rates for these 2 types of infection were 50% and 100%, respectively. During the same period, there was an overall mortality of 1.7% (n=5). No surviving patient lost graft function. CONCLUSION: Although fungal and mycobacterial infections caused significant mortality, the overall incidence remains low and comparable to that associated with other induction agents.

Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia.

BACKGROUND: Liver ischemia and reperfusion injury is associated with activation of multiple inflammatory pathways, including free radicals, cytokines, and neutrophil-mediated tissue damage among others. Tacrolimus (FK506) has shown important regulatory effects on some inflammatory pathways, such as cytokines, neutrophils, and adhesion molecules. In this study, we explored a new potential protective mechanism for tacrolimus in the liver inflammatory response after ischemia and reperfusion, specifically its effect on liver tissue free radicals. METHODS: Total hepatic ischemia was produced in the rat for 90 min with an extracorporeal portosystemic shunt. Animals (n=96) were divided into four groups: group 1 comprised normal rats for reference values; group 2 comprised sham operated rats; in group 3, ischemic control rats received only the vehicle; and the experimental treatment group, group 4, received tacrolimus at a dose of 0.3 mg/kg, 4 hr before ischemia. Animal survival was followed up to 7 days. Liver function tests were performed and liver tissue free radicals and myeloperoxidase, serum cytokines (interleukin 1, tumor necrosis factor-alpha), and liver histology were measured 4 hr after reperfusion. RESULTS: Seven-day survival was significantly improved from only 20% in the control group to 55% in the tacrolimus group (P<0.01). Liver function tests, histology, and myeloperoxidase tissue values were significantly improved (P<0.05) with tacrolimus pretreatment. Furthermore, a significant (P<0.05) down-regulation of serum cytokines and liver tissue free radicals was observed. CONCLUSIONS: These data indicate a new and different protective mechanism for FK506 in regard to its ability to down-regulate free radical levels in livers subjected to severe ischemia and reperfusion. Tacrolimus, also confirmed to be a potent suppressor of the cytokine response, specifically interleukin 1 and tumor necrosis, decreased neutrophil tissue migration as well.

Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusion.

BACKGROUND: The selectin family of adhesion molecules plays a key role in the neutrophil-mediated injury observed after ischemia and reperfusion. In our study, we investigated the effects of TBC-1269, a novel small-molecule, nonoligosaccharide inhibitor of P-, E-, and L-selectin binding, in the liver inflammatory response after 90 minutes of warm ischemia. STUDY DESIGN: Total liver ischemia was produced in Sprague-Dawley rats for 90 minutes using an extracorporeal portosystemic shunt. The animals were divided into five groups including: the sham (group 1), ischemic control (group 2) receiving only the vehicle, and the treated groups receiving TBC-1269 at a dose of 25 mg/kg at different times of administration: 15 minutes before reperfusion (group 3), at reperfusion (group 4), and 15 minutes after reperfusion (group 5). The following indices were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology. RESULTS: TBC-1269 treated groups experienced a significant increase in survival compared with controls. Best overall survival, 70%, was observed when TBC-1269 (Texas Biotechnology Corporation, Houston, TX) was administered 15 minutes before reperfusion (p < 0.05). This group also showed a marked decrease (p < 0.05) in liver enzyme levels at 6 hours after reperfusion. Neutrophil migration was also significantly ameliorated (81%), as reflected by decreased myeloperoxidase levels. We observed improved histologic damage scores in the treated group compared with controls (p < 0.05). CONCLUSIONS: A small-molecule selectin inhibitor (TBC-1269) had a protective effect in livers subjected to 90 minutes of warm hepatic ischemia and 6 hours of reperfusion by decreasing neutrophil infiltration, migration and subsequent tissue damage. The best protective effect was achieved when the compound was administered 15 minutes before reperfusion. These findings offer a new therapeutic alternative for protection against ischemia and reperfusion injury.

Sialyl Lewis(x) analog improves liver function by decreasing neutrophil migration after hemorrhagic shock.

BACKGROUND: Little is known about the changes in the hepatic microcirculation and the leukocyte-endothelial adhesion processes during the early reperfusion period after resuscitation in hemorrhagic shock. P-selectin and its natural ligand Sialyl Lewis(x) (SLe(x)) are involved in the early stages of reperfusion events leading to neutrophil migration. Therefore, the aim of this study was to investigate the effect of the administration of CY-1503 [corrected], a synthetic SLe(x) analog, in the liver inflammatory response and neutrophil migration after hemorrhagic shock. MATERIALS AND METHODS: Rats, each weighing 275 to 300 grams, were subjected to 60 minutes of pressure controlled hemorrhagic shock. After this period, animals were resuscitated according to the following protocol: shed blood was reinfused to equal 50% of the total volume bled, and the other 50% was replaced with 3x volume of Ringer's lactated solution. Animals were divided into sham and two study groups to receive vehicle (controls) and CY-1503 [corrected] (10 mg/kg intravenously) diluted in 1 mL of normal saline 45 minutes after initiating hemorrhagic shock. The following parameters were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology. RESULTS: Survival was significantly increased from 48% in the controls to 90% in the CY-1503 [corrected] treated group. Animals treated with the SLe(x) analog showed significantly better mean arterial blood pressure after 15 minutes after resuscitation. Also, the treated group showed a marked decrease in liver enzymes levels at 5 minutes and 4 hours after reperfusion. Neutrophil migration was significantly ameliorated as reflected by decreased myeloperoxidase levels in the SLe(x) analog treated group. Furthermore, we observed improved histologic damage scores in the treated group when compared with controls. CONCLUSIONS: The SLe(x) analog, CY-1503 [corrected], had a protective effect in ischemic livers by decreasing neutrophil migration after hemorrhagic shock and resuscitation. This protective effect also resulted in improved survival and mean arterial blood pressure after resuscitation.

21-Aminosteroids block neutrophil infiltration and provide liver protection independent of NO2-/NO3- levels.

21-Aminosteroids are antioxidant compounds that prevent iron-dependent lipid peroxidation and improve cell viability. In this work we attempt to define the role of 21-aminosteroids in liver ischemia and reperfusion and assess their possible mode of action, specifically their effect on neutrophil infiltration and nitrite/nitrate levels. Total liver ischemia for 90 min was produced in the rat with the use of a portosystemic shunt. Three groups of animals were studied. One group received the 21-aminosteroid U-74389G (10 mg/ kg) divided into two equal doses 10 min prior to ischemia (7 mg/kg) and 10 min before reperfusion (3 mg/ kg). The two other groups included the sham and the control animals. We studied survival at 7 days and serum liver enzymes, liver myeloperoxidase, plasma nitrites, nitrates, and liver histology at 6 hr postreperfusion. Animal survival improved from 13% in the ischemic control to 52% in the lazaroid treated group (P < 0.05). We observed significant improvements in liver function tests, liver myeloperoxidase levels, as well as in the liver histology (P < 0.05). We could not find statistical difference in plasma nitrite/nitrate (P > 0.1). The 21-aminosteroids significantly improved animal survival after total liver ischemia, through a mechanism that includes blocking neutrophil infiltration which is independent from nitrite/nitrate levels.

Sulfo-Lewis(x) diminishes neutrophil infiltration and free radicals with minimal effect on serum cytokines after liver ischemia and reperfusion.

BACKGROUND: Cell adhesion plays a central role in the pathogenesis of neutrophil-induced hepatic injury after ischemia and reperfusion. Sialyl Lewis(x) binds to selectins mediating neutrophil adherence to endothelium, thereby facilitating subsequent migration and tissue damage. AIM: We studied the effect of a novel sulfo-derivative of sialyl Lewis(x), GM-1998, on the liver inflammatory response after ischemia and reperfusion. Specifically, we evaluated its impact on three key inflammatory mediators: neutrophil migration, free radicals, and serum cytokines. MATERIAL AND METHODS: Rats were subjected to total hepatic ischemia for 90 min using an extracorporeal portosystemic shunt to avoid splanchnic congestion. GM-1998 was given at a total dose of 20 mg/kg both prior to and after reperfusion. Liver function tests, liver tissue free radicals, and myeloperoxidase (MPO), serum cytokines (IL-1, TNF-alpha), and liver histology were analyzed 4 hr after reperfusion. Additionally, survival was followed for up to 7 days. RESULTS: Seven-day survival significantly increased from 20% in the control group to 65% in the sulfo-Lewis(x) treated group. Liver function tests and histological damage scores were improved in comparison to controls. We observed significant downregulation of free radicals and neutrophil migration. This compound did not significantly affect serum cytokine levels. CONCLUSIONS: GM-1998 showed a protective effect in an in vivo model of severe liver ischemia and reperfusion by decreasing tissue free radical levels and selectin-mediated neutrophil migration. This protective effect was also reflected in improved liver function tests and histological response leading to better survival. We confirmed the beneficial effect of neutrophil blockade as a key target to prevent damage after the reperfusion phenomenon by using a glycomimetic sulfo-Lewis(x).