tacrolimus and Short-Bowel-Syndrome

Intestinal transplantation has been gradually instituted in the management of intestinal failure. More than 200 cases including isolated intestinal transplant, liver/intestinal transplant, and multivisceral transplant have been performed worldwide,with 1-year graft and patient survival rates of 66% and 54%,respectively. Indications for the procedure include short bowel syndrome and functional abnormalities secondary to a variety of diseases or conditions. Tacrolimus-based immunosuppression regimens have been used universally with improved outcomes. The major contributors to the morbidity and mortality include rejection,infection, and technical complications. Of those, control of rejection remains the most difficult dilemma and it will be the key to improved patient and graft survival.

Topics: Digestive System Surgical Procedures; Graft Rejection; Humans; Intestines; Liver Transplantation; Patient Selection; Postoperative Care; Postoperative Complications; Short Bowel Syndrome; Survival Rate; Tacrolimus; Tissue Donors; Treatment Outcome

  We report a case series of four children who developed fixed dilated pupils associated with high tacrolimus levels (>30 nanograms/millilitre [ng/mL]) in the immediate post-operative period following isolated liver or liver and small bowel transplantation.

Topics: Child; Cystic Fibrosis; Electroencephalography; Female; Fixation, Ocular; Humans; Immunosuppressive Agents; Infant; Liver Failure, Acute; Liver Transplantation; Male; Pupil; Short Bowel Syndrome; Tacrolimus

Topics: Adult; Child; Child, Preschool; Female; Follow-Up Studies; Graft Survival; Humans; Intestinal Diseases; Intestine, Small; Liver Failure; Liver Transplantation; Male; Parenteral Nutrition, Total; Retrospective Studies; Short Bowel Syndrome; Survival Analysis; Tacrolimus; Time Factors

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft-versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection.

Topics: Adult; Alprostadil; Child, Preschool; Female; Gastrointestinal Motility; Graft Rejection; Graft vs Host Disease; Humans; Infant; Intestinal Absorption; Intestinal Diseases; Intestine, Small; Intestines; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Parenteral Nutrition; Postoperative Complications; Short Bowel Syndrome; Surgical Wound Infection; Survival Rate; Tacrolimus

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Infections; Inflammation; Intestinal Mucosa; Intestine, Small; Intestines; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Neuromuscular Diseases; Postoperative Complications; Regeneration; Short Bowel Syndrome; Tacrolimus; Transplantation; Treatment Outcome

Topics: Administration, Oral; Adolescent; Humans; Immunosuppressive Agents; Injections, Intravenous; Liver Transplantation; Living Donors; Male; Short Bowel Syndrome; Tacrolimus

Early diagnosis and treatment of acute cellular rejection (ACR) after intestinal transplantation (ITx) is challenging. We report the outcome of three patients: two presented mild ACR improved with steroids. One presented steroid-resistant severe rejection, improved after rabbit anti-thymocyte globulin (r-ATG), but unfortunately died for encephalitis caused by opportunistic infections.

Topics: Adolescent; Anastomosis, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Child; Daclizumab; Encephalitis; Fatal Outcome; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Intestinal Diseases; Intestinal Volvulus; Intestines; Male; Nervous System Diseases; Recombinant Fusion Proteins; Short Bowel Syndrome; Tacrolimus

Short-bowel syndrome (SBS) is defined as the malabsorptive state that occurs after extensive resection of the small intestine. In patients with SBS, oral administration of drugs usually becomes difficult because of the severity of intestinal failure. We describe a successful living related renal transplantation (LRRTx) in an 18-year-old male with SBS. Shortly after birth, the patient developed necrotizing enterocolitis requiring massive resection of the small intestine, which resulted in SBS. At seven years of age, the patient developed proteinuria and was diagnosed as focal segmental glomerulosclerosis (FSGS). His kidney function was gradually deteriorated toward the end-stage renal failure. The patient received LRRTx at age of 18 years. To evaluate the absorption capacity of the patient, we investigated pharmacokinetics of calcineurine inhibitors (tacrolimus and cyclosporine). The drug concentration, which is sufficient to provide effective immunosuppression, was achieved with cyclosporine, but not with tacrolimus. The patient therefore received a triple immunosuppressive therapy with oral cyclosporine, methyl-prednisolone and mycophenolate mofetil. To prevent both recurrent FSGS and rejection, we repeatedly analyzed the trough level and the pharmacokinetics of cyclosporine after LRRTx. The patient was successfully treated with oral immunosuppression for over 5 years, without hemodialysis. To our knowledge, this is the first report showing the long-term outcome of LRRTx treated with oral cyclosporine in a patient with SBS.

Topics: Administration, Oral; Adolescent; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Quality of Life; Short Bowel Syndrome; Tacrolimus; Treatment Outcome

Small bowel transplantation is associated with a patient survival at one and five years, of 80% and 63%, respectively. We report a 36 year-old female with short bowel syndrome, subjected to the first small bowel transplantation performed in Chile. A cadaveric gran was used. Immunosuppression was achieved by means of alemtuzumab, tacrolimus, sirolimus, micofenolate mofetil and steroids. Serial endoscopies and biopsies were performed during seven months after transplantation. The most important late complications were a drug induced renal failure, infections caused by opportunistic agents and a gastrointestinal bleeding probably induced by drugs. After 29 months of follow up, the patient is ambulatory, on oral diet only and with no evidence of graft rejection.

Topics: Adult; Chile; Female; Graft Rejection; Humans; Immunosuppressive Agents; Intestine, Small; Short Bowel Syndrome; Tacrolimus

Graft rejection is a serious complication after intestinal and multivisceral transplantation. Classic anti-rejection strategies often focus on addressing the cellular component, however mounting evidence suggests that antibody mediated rejection may also play an important role in patient and graft survival. Bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, has been found to be useful in treating antibody mediated rejection in kidney transplant recipients. The following case illustrates how bortezomib was used to successfully reverse refractory rejection in a patient following multivisceral transplantation. While the rejection was able to be controlled, this patient's course was complicated by an aggressive viral infection after bortezomib therapy. Bortezomib may be a useful agent in the treatment of rejection after intestinal and multivisceral transplantation; however more data is needed to assess its impact on infectious complications in this complex group of patients.

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Biopsy; Boronic Acids; Bortezomib; Child, Preschool; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Intestines; Protease Inhibitors; Pyrazines; Short Bowel Syndrome; Tacrolimus; Treatment Outcome; Viscera

Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD).. To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx).. A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function).. Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06).. Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.

Topics: Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Methylprednisolone; Prednisolone; Retrospective Studies; Short Bowel Syndrome; Statistics, Nonparametric; Tacrolimus

Achieving adequate oral immunosuppression in a renal transplant patient who develops short bowel syndrome provides a significant challenge. We report a case where oral tacrolimus has been used to provide immunosuppression in an established renal transplant patient who developed short bowel syndrome secondary to mesenteric infarction. After reviewing the literature, we conclude that tacrolimus can be used as first-line immunosuppression in patients with short bowel syndrome.

Topics: Administration, Oral; Adult; Female; Humans; Immunosuppressive Agents; Infarction; Kidney Transplantation; Short Bowel Syndrome; Splanchnic Circulation; Tacrolimus

Topics: Administration, Oral; Anastomosis, Surgical; Animals; Area Under Curve; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Ileum; Immunosuppressive Agents; Intestinal Absorption; Intestinal Mucosa; Jejunum; Ketoconazole; Metabolic Clearance Rate; Mixed Function Oxygenases; Short Bowel Syndrome; Swine; Tacrolimus

To establish a safe and effective usage of oral tacrolimus (FK506) in small bowel transplantation (SBTx) recipients, trough levels and area under the curve (AUC) values of FK506 were assessed using swine models of SBTx and short bowel. Thirty-eight Landrace male piglets were divided into four groups as follows: Group 1, controls (n=13); Group 2, a one-third small bowel model (n=5); Group 3, a short bowel model (n=10); and Group 4, a one-third small bowel allograft model (n=10; five donors and five recipients). Piglets of Groups 1 and 3 were further divided into two sub-groups, according to the route of drug administration: Groups 1a (n=10) and 3a (n=7) received FK506 orally, and Groups 1b (n=3) and 3b (n=3) received FK506 intravenously. Oral or intravenous FK506 was started on post-operative day 3 and continued until day 7 in each group. On day 7, trough levels and AUC values were measured. In Groups 1a, 2, 3a and 4, trough levels of FK506 were 2.1+/-1.2 (p<0.01 vs. Group 2, 3a or 4), 11.2+/-2.1, 23.3+/-4.8 (p<0.05 vs. Group 2 or 4) and 14.6+/-3.0 ng/mL, and AUC values were 101+/-90 (p<0.01 vs. Group 3a or 4), 319&+/-155, 808+/-200, and 531+/-113 ng.h/mL, respectively. Both trough levels and AUC values were lowest in Group 1a and highest in Group 3a. Between Groups 1b and 3b, there was no significant difference in the blood levels of intravenous FK506. The shorter the functioning residual small intestine was, the higher the trough level of oral FK506 was, while the presence or absence of small intestine did not affect blood levels of intravenous FK506. These results suggest that oral FK506 is metabolized in the functioning small intestine during its absorption. Therefore, events which cause intestinal malfunction, such as graft rejection in SBTx, inflammation and loss of small intestine, may adversely raise the trough level of oral FK506.

Topics: Animals; Area Under Curve; Intestine, Small; Male; Models, Animal; Short Bowel Syndrome; Swine; Tacrolimus

We describe two children with intestinal failure due to short or absent small bowel who underwent isolated liver transplantation for liver disease related to parenteral nutrition. Both received reduced-size liver grafts whilst awaiting a suitable small bowel donor. Immunosuppressive therapy was based on oral tacrolimus and intravenous steroids. Therapeutic levels of tacrolimus were achieved at low dosage of 0.14-0.28 mg/kg per day. Median and mean blood tacrolimus levels were 9.9 and 13.7 ng/ml (range 4.9-42.3 ng/ml) in case 1 and 5.8 and 7.2 ng/ml (range 1-30 ng/ml) in case 2 before small bowel transplantation, respectively. Following small bowel transplantation, levels were 17.1 and 20.1 ng/ml (range 9.2-30 ng/ml), with oral doses of 0.54-1.35 mg/kg per day. Both children died of adenovirus pneumonia, with functioning grafts. Our experience demonstrates that effective levels of immunosuppression can be achieved by oral administration of tacrolimus in children with short or absent small bowel.

Topics: Adenoviridae Infections; Administration, Oral; Child, Preschool; Colon; Cyclosporine; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Absorption; Intestinal Atresia; Intestine, Small; Liver Failure; Liver Transplantation; Male; Parenteral Nutrition; Pneumonia, Viral; Postoperative Complications; Short Bowel Syndrome; Tacrolimus

Topics: Adult; Blue Cross Blue Shield Insurance Plans; Child; Drug Approval; Humans; Immunosuppressive Agents; Intestine, Small; Outcome Assessment, Health Care; Parenteral Nutrition, Total; Registries; Short Bowel Syndrome; Survival Rate; Tacrolimus; Technology Assessment, Biomedical; United States; United States Food and Drug Administration; Viscera

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestine, Small; Liver Failure; Parenteral Nutrition; Short Bowel Syndrome; Tacrolimus; Transaminases

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

Intestinal transplants using cadaver donors have become an alternative to total parenteral nutrition (TPN) for the treatment of irreversible intestinal failure. Intestinal transplants using living-related donors have rarely been attempted, and the surgical technique has not been standardized.. We performed a living-related intestinal transplant for a paraplegic, 16-year-old boy with life-threatening TPN complications, including lack of vascular access, recurrent line infections, and intermittent liver dysfunction.. A four antigen-matched donor (father) underwent resection of 200 cm of the ileum on a vascular pedicle comprising the ileocolic artery and vein. This resection left the donor with 300 cm of proximal small bowel, 20 cm of the most distal terminal ileum, the ileocecal valve, and all of the large intestine. The donor's ileocolic artery and vein were anastomosed to the recipient's infrarenal aorta and cava; bowel continuity was restored with an end-to-end anastomosis between the recipient's jejunum and the donor's ileum. Both donor and recipient had uneventful postoperative courses. Recipient maintenance immunosuppression has been with tacrolimus, mycophenolate mofetil, and prednisone. One year after transplant, urine methylmalonic acid indicates good vitamin B12 absorption in both the donor and recipient. The recipient has been completely off TPN since discharge (posttransplant day 21), has gained 20 kg, and has had no evidence of rejection, infection, or graft-versus-host disease.. Intestinal transplants from living-related donors can be lifesaving for selected patients with chronic intestinal failure and can be done with minimal risk to the donor.

Topics: Adolescent; Anastomosis, Surgical; Cholestasis; Histocompatibility Testing; Humans; Immunosuppressive Agents; Intestines; Living Donors; Male; Methylmalonic Acid; Middle Aged; Paraplegia; Parenteral Nutrition, Total; Short Bowel Syndrome; Tacrolimus

Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Intestine, Small; Middle Aged; Parenteral Nutrition, Total; Short Bowel Syndrome; Tacrolimus; Transplantation, Homologous