tacrolimus and Shock

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Diclofenac; Fatal Outcome; Female; Femoral Vein; Graft Survival; Humans; Immunosuppression Therapy; Intermittent Claudication; Intestines; Liver Failure; Liver Transplantation; Middle Aged; Popliteal Vein; Shock; Steroids; Tacrolimus; Treatment Outcome

Infection due to cytomegalovirus (CMV) is the most frequent opportunistic infection following renal transplantation (RT). It is usually asymptomatic. Cytomegalovirus disease causes fever leucopenia, thrombocytopenia and slightly elevated transaminases. The development of severe invasive forms is uncommon nowadays with post-transplantation monitoring, prophylactic regimens in high-risk patients and early treatment with ganciclovir. We report two renal transplant recipients who presented with severe gastrointestinal bleeding as the first manifestation of CMV disease at 9 and 14 weeks after transplantation. In both patients repeated post-transplantation pp65 antigenemia monitoring was negative. One patient developed hypovolemic shock due to severe rectal bleeding; an atypical bleeding ulcer was detected in the ileocecal valve. The other patient presented with upper gastrointestinal hemorrhage from a bleeding duodenal ulcer. Histological and immunohistochemical study confirmed the diagnosis. Both patients were elderly and on triple therapy with tacrolimus, mycophenolate and prednisone. We discuss the role of mycophenolate and the new immunosuppressant agents as factors favoring a state of enhanced immunosuppression, which may facilitate the onset of severe atypical forms of CMV disease.

Topics: Aged; Cytomegalovirus; Cytomegalovirus Infections; Disease Susceptibility; Duodenal Ulcer; Gastrointestinal Hemorrhage; Humans; Ileal Diseases; Ileocecal Valve; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Postoperative Complications; Prednisone; Shock; Tacrolimus; Ulcer

1. Tumour necrosis factor (TNF-alpha) is a pleiotropic cytokine which is deeply involved in the pathogenesis of splanchnic artery occlusion (SAO) shock. Tacrolimus, formerly known as FK506, is a macrolide antibiotic, that blocks the transcription of several proinflammatory cytokines including TNF-alpha. 2. Male anaesthetized rats were subjected to clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (SAO shock). Sham operated animals were used as controls. SAO shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham shocked rats survived more than 4 h), enhanced serum TNF-alpha concentrations (415+/-12 U ml(-1)), decreased mean arterial blood pressure (MAP), leukopenia and increased ileal leukocyte accumulation studied by means of myeloperoxidase activity (MPO=7.5+/-0.3 U g(-1) tissue). Moreover aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM - 10 microM), reduced responsiveness to acetylcholine (ACh, 10 nM - 10 microM) and increased staining for intercellular adhesion molecule-1 (ICAM-1). Furthermore increased mRNA for TNF-alpha was observed in peritoneal macrophages of SAO shocked rats. 3. Tacrolimus (100 microg kg(-1), 5 min after splanchnic arteries occlusion) increased survival rate (SAO + Tacrolimus = 100% at 4 h of reperfusion), reverted the marked hypotension, reduced serum TNF-alpha (15+/-3 U ml(-1)), ameliorated leukopenia, reduced ileal MPO (0.9+/-0.01 U g(-1) tissue), restored to control values the hyporeactivity to PE. improved the reduced responsiveness to ACh and blunted the enhanced immunostaining for ICAM-1 in the aorta. Finally tacrolimus suppressed cytokine mRNA levels in peritoneal macrophages. 4. The data suggest that tacrolimus may represent a new therapeutic approach in circulatory shock.

Topics: Animals; Blood Pressure; Constriction, Pathologic; Endothelium, Vascular; Immunohistochemistry; Immunosuppressive Agents; Leukocyte Count; Macrophages; Male; Muscle Contraction; Muscle, Smooth, Vascular; Peroxidase; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Shock; Splanchnic Circulation; Survival Analysis; Tacrolimus; Tumor Necrosis Factor-alpha

A murine paratopic model of intestinal transplantation was developed and used to study the immune response to allografts in normal C57BL/6 recipients (H2(b)) and C57BL/6 recipients treated with tacrolimus (1 mg/kg, Days 0-7). B6C3F1 mice (C57BL/6 x C3H/HeJ, H2(bxk)) were used as donors. The paratopic model differed from the standard heterotopic model in that continuity of the intestine graft with the recipient intestine was established by anastomosing the graft ileum to the side of the recipient jejunum. The success rate of this modified procedure was 82% (94/114). Major complications included hypovolemic shock and/or anesthetic-related deaths (8%), infection (8%), and vascular thrombosis (2%). Rejection was assessed using both clinical features (i.e., edema and closure of the stoma, mucous discharge, and a palpable mass) and histologic features (apoptosis of crypt cells, crypt destruction, lymphocytic infiltrate, and mucosal ulceration). Syngeneic grafts appeared clinically and histologically normal throughout the study period. Untreated recipients of allografts developed clinical and histologic evidence of rejection by Day 4 which progressed to severe rejection and graft destruction by Day 18. After initially developing evidence of mild to moderate graft rejection on Day 8, the severity of allograft rejection decreased significantly by Days 10 to 14 in tacrolimus-treated mice. By Day 28 evidence of moderate rejection had recurred in mice treated with an 8-day course of tacrolimus. Consistent with these observations, graft function, as assessed by maltose absorption, was impaired in rejecting allografts when compared with syngeneic grafts. Allografts in mice treated with tacrolimus demonstrated improved maltose absorption relative to allografts from untreated mice. These studies describe a modified technique for intestinal transplantation in mice and provide a detailed analysis of complications as well as an assessment of rejection and its functional consequences. Based on these results, we conclude that the paratopic model of intestinal transplantation in mice is a useful tool for studying the host immune response to intestinal allografts.

Topics: Animals; Digestive System Surgical Procedures; Graft Rejection; Immunosuppressive Agents; Intestinal Absorption; Intestine, Small; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Models, Biological; Shock; Surgical Wound Infection; Tacrolimus; Thrombosis; Transplantation, Homologous; Transplantation, Isogeneic