tacrolimus and Multiple-Organ-Failure

Paraneoplastic pemphigus (PNP) or paraneoplastic autoimmune multiorgan syndrome (PAMS) is a life-threatening autoimmune blistering disease commonly associated with lymphoproliferative neoplasms. This article focuses on current management strategies in PNP/PAMS, and reported instances of their treatment successes and failures. Due to the rarity of the condition and the high rates of treatment failure, no randomized control trials exist to guide the evidence-based treatment of this condition; all evidence to date on the efficacy of therapeutic modalities has been gained from individual case reports, small case series, and expert recommendations.

Topics: Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Autoimmune Diseases; Azathioprine; Cyclophosphamide; Cyclosporine; Dermatologic Agents; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Multiple Organ Failure; Mycophenolic Acid; Paraneoplastic Syndromes; Pemphigus; Plasmapheresis; Rituximab; Tacrolimus

Neurotoxicity represents a serious complication following orthotopic liver transplantation. Neurotoxicity may be evoked by various perioperative factors or develop due to drug-specific toxicity of immunosuppression. We evaluated the incidence of neurotoxicity in 121 patients, 61 randomly assigned to FK506 and 60 to CsA-based immunosuppression. The incidence of moderate or severe neurotoxicity was markedly higher in patients treated with FK506 in the early postoperative period (21.3% vs. 11.7% in patients receiving CsA), after retransplantation (100% vs. 0% in patients receiving CsA), and late (8 of 10 patients; P < or = 0.05 vs. CsA). Furthermore late neurotoxicity was highly associated with severe infections and MOFS, which had a lethal outcome in more than 50% of the patients. Patients who subsequently died developed neurologic symptoms in 67% of the cases. These patients also experienced moderate or severe neurotoxicity significantly more often in the early postoperative period compared with patients with a successful outcome (50% vs. 17.3%; P < or = 0.01). However, various blood and serum parameters, including ALT, bilirubin, urea, creatinine and glucose, when analyzed alone or in multivariate fashion, also correlated significantly with the incidence and severity of early postoperative neurotoxicity, indicating that neurotoxicity following LTX may be caused by various factors and is not exclusively a drug-specific side effect of immunosuppression.

Topics: Adolescent; Adult; Aged; Blood Chemical Analysis; Brain; Brain Diseases; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Infections; Liver Transplantation; Male; Middle Aged; Multiple Organ Failure; Reoperation; Tacrolimus

Nephrotoxicity represents a serious side effect of immunosuppression following liver transplantation. In order to compare the nephrotoxic action of CsA and FK506 in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 of whom were randomly assigned to CsA- and 61 to FK506-based immunosuppression. Early postoperative renal insufficiency (between PODs 0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (38.3%) and FK506 (42.6%). Early postoperative acute renal failure (ARF) (SCr > 3 mg/dl) was observed in 18.0% of patients in the FK506 treatment group and 18.3% of patients receiving CsA therapy. Approximately half the patients with ARF required hemodialysis (CsA: 11.7%; and FK506: 8.2%). All patients with early postoperative ARF requiring hemodialysis survived for more than one year. New onset of late ARF (between PODs 30 and 365) was observed in 6.6% of patients receiving FK506 therapy and in 1.7% in the CsA treatment group as a result of severe infection with multiple organ failure syndrome (MOFS). There was 100% mortality in patients with late ARF requiring hemodialysis. Etiology and prognosis of early and late ARF seem to be completely different. Early ARF was associated with severe coagulopathy and a rise in bilirubin and free hemoglobin, and was accompanied by impaired liver function. Mean onset of hemodialysis in CsA-treated patients was POD 1 and in FK506-treated patients POD 6, which disclosed a different time course of drug-specific nephrotoxicity of CsA and FK506 in early ARF. In contrast, late ARF occurred in both treatment groups only as a part of the MOFS in association with severe infections, an observation consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity of CsA and FK506. These preliminary results demonstrate a similar outcome in terms of both early and late nephrotoxicity, but longer follow-up will delineate the overall efficacy and toxicity in humans.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Cyclosporine; Female; Graft Rejection; Humans; Infections; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Multiple Organ Failure; Renal Dialysis; Tacrolimus

Posterior reversible encephalopathy syndrome is a neurotoxic state accompanied by unique brain imaging patterns and neurologic abnormalities, typically associated with several complex clinical conditions such as preeclampsia/eclampsia, solid-organ transplant procedures, autoimmune diseases, and immunosuppressive agents. The detailed mechanism of posterior reversible encephalopathy syndrome is not known, and the current therapy is only supportive care. Here, we present a 33-year-old parturient woman with preeclampsia complicated with hemolysis, elevated liver enzymes, and low platelet syndrome, fulminant hepatitis B, acute fatty liver, and posterior reversible encephalopathy syndrome. The patient developed gross hepatic infarction soon after liver transplant. After several possible causes were excluded, we found that progression of underlying posterior reversible encephalopathy syndrome-induced endothelial damage by overdose of tacrolimus may have been the major cause for deteriorating hypoperfusion of the transplanted liver and fatal graft failure. In liver transplant recipients, severe posttransplant hypoperfusion of the grafted liver may result in loss of the liver allograft and even mortality. Poor control of underlying posterior reversible encephalopathy syndrome-associated endothelial damage because of tacrolimus overdose may lead to severe hypoperfusion of grafted hepatic vessels and subsequent hepatic infarction. This report highlights tacrolimus as a potential trigger of posterior reversible encephalopathy syndrome and may inform clinical decisions regarding tacrolimus administration in liver transplant recipients with preexisting or newly developed posterior reversible encephalopathy syndrome.

Topics: Adult; Calcineurin Inhibitors; Disease Progression; Drug Overdose; Fatal Outcome; Female; Hepatic Infarction; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Multiple Organ Failure; Posterior Leukoencephalopathy Syndrome; Pregnancy; Tacrolimus

Pseudomonas aeruginosa Exotoxin A (PEA) induces hepatotoxicity in experimental animals. Lipopolysaccharide (LPS) interacts synergistically with xenotoxics to induce severe organ injury. We examined the combination of non-injurious doses of LPS and sub-hepatotoxic PEA in the induction of multiple organ injury (MOI). Rats treated with 20 or 40 microg/kg LPS plus 10 microg/kg PEA developed severe liver, kidney, and lung injury; elevation of TNF-alpha, IFN-gamma, and IL-2; and high mortality. Depletion of Kupffer cells or T-cells by pretreatment with Gadolinium Chloride or FK506, respectively, attenuated MOI. Thus LPS + PEA acted synergistically on Kupffer and T-cells to induce proinflammatory cytokines contributing to MOI.

Topics: ADP Ribose Transferases; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Bacterial Toxins; Blood Urea Nitrogen; Creatinine; Cytokines; Drug Synergism; Exotoxins; Gadolinium; Kidney; Kupffer Cells; Lipopolysaccharides; Liver; Lung; Male; Multiple Organ Failure; Pseudomonas aeruginosa Exotoxin A; Rats; Rats, Wistar; Survival Rate; T-Lymphocytes; Tacrolimus; Virulence Factors

Relative adrenal insufficiency is now a well-known clinical condition that occurs in critically ill patients particularly with septic complication. However, this pathology has long been unrecognized until recently in liver transplantation patients, for whom postoperative immunosuppressive therapies almost always comprise corticosteroids. We report an obvious case of relative adrenal insufficiency manifested by severe multiple organ dysfunction in a recipient after living donor liver transplantation (LDLT). A 38-year-old woman with multiple hepatocellular carcinoma developed refractory liver failure 2 months after the completion of the dual treatment; namely a cytoreductive right hepatectomy for bulky main tumors followed by 2 courses of percutaneous isolated hepatic perfusion for residual tumors in the remnant liver. She underwent a right-lobe LDLT, and postoperative immunosuppression was initiated with a low-dose tacrolimus monotherapy without corticosteroid because of a severe septic condition before transplantation. Postoperatively, she developed progressive hyperbilirubinemia, renal dysfunction, and coagulopathy. As the corticotropin stimulation test suggested the relative adrenal insufficiency, corticosteroid was commenced 40 days after LDLT. Thereafter, multiple organ dysfunction resolved dramatically and promptly. The patient is presently alive and well with completely normalized liver function 45 months after LDLT.

Topics: Adrenal Insufficiency; Adult; Carcinoma, Hepatocellular; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Methylprednisolone; Multiple Organ Failure; Postoperative Complications; Radiography, Abdominal; Tacrolimus; Tomography, Spiral Computed

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogeneous EBV-related disorder, ranging from mild/moderate forms to rapidly lethal disorders. The lethal form of CAEBV is characterized by multiple organ failure, hemophagocytic syndrome, and development of lymphomas. Allogeneic stem cell transplantation is considered as the only potentially curative treatment for the lethal form of CAEBV, but it is not always desirable because of the high incidence of regimen-related toxicities. A 17-year-old female with CAEBV, who was refractory to conventional therapies and considered to be unable to receive a myeloablative regimen because of multiple organ dysfunction, underwent allogeneic nonmyeloablative stem cell transplantation (allo-NST) before developing a hematological malignancy. She has been well without any signs of CAEBV for 27 months after allo-NST, and we confirmed that specific cytotoxic T lymphocyte activity against EBV was reconstituted. This outcome suggests that allo-NST can control CAEBV by reconstituting the host immunity against EBV.

Topics: Adolescent; B-Lymphocytes; Cell Line, Transformed; Cell Transformation, Viral; Chronic Disease; Cyclosporine; DNA, Viral; Drug Resistance; Epstein-Barr Virus Infections; Etoposide; Female; Hepatitis, Viral, Human; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Multiple Organ Failure; Peripheral Blood Stem Cell Transplantation; T-Lymphocytes, Cytotoxic; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Tacrolimus is increasingly used for graft-versus-host disease (GVHD) prophylaxis and therapy in the allogeneic stem cell transplant (allo-SCT) setting. Pancreatitis, previously described as a side-effect of cyclosporine, has not been reported in allo-SCT recipients receiving tacrolimus. We present here a case of acute pancreatitis in a 28-year-old patient with chronic myelogenous leukemia (CML) who received an unrelated umbilical cord blood transplant (UCBT) and tacrolimus for GVHD prophylaxis. On day +31 post-transplant, she developed severe acute pancreatitis with multiorgan failure, from which she recovered completely. Tacrolimus was the probable cause of pancreatitis in this patient.

Topics: Adult; Female; Fetal Blood; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Multiple Organ Failure; Pancreatitis; Renal Dialysis; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

An 8-month-old child with an immunodeficiency disorder characterized by abnormal lymphocyte function and by low IgG and IgA levels had combined liver and small bowel transplantation under tacrolimus and steroid immunosuppression for the treatment of short gut syndrome and hepatic cirrhosis. The patient developed an early postoperative episode of Pneumocystis carinii pneumonia, and a subsequent surgical complication, prompting discontinuance of tacrolimus. A skin rash eventually shown to be graft-versus-host disease (GVHD) developed in the flank on the 12th post-transplant day and gradually became generalized. Peritonitis, sepsis, multisystem organ failure including the liver allograft led to death on the 23rd post-operative day. The mechanisms leading to post-transplant GVHD under the specific circumstances in this case are discussed.

Topics: Exanthema; Fatal Outcome; Female; Glucocorticoids; Graft vs Host Disease; Humans; IgA Deficiency; IgG Deficiency; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Intestine, Small; Ischemia; Liver; Liver Cirrhosis; Liver Transplantation; Lymphocytes; Methylprednisolone; Multiple Organ Failure; Peritonitis; Pneumonia, Pneumocystis; Sepsis; Short Bowel Syndrome; Tacrolimus

Topics: Anti-Bacterial Agents; Bronchoalveolar Lavage; Contraindications; Cyclosporine; Female; Graft Rejection; Humans; Liver Transplantation; Middle Aged; Multiple Organ Failure; Sepsis; Tacrolimus