tacrolimus and Intestinal-Diseases

With increasing survival rates, intestinal transplantation (ITx) and multivisceral transplantation have reached the mainstream of medical care. Pediatric candidates for ITx often suffer from severe multisystem impairments that pose challenges to the medical team. These patients frequently require intensive care preoperatively and have unique intensive care needs postoperatively.. We reviewed the literature on intensive care of pediatric intestinal transplantation as well as our own experience. This review is not aimed only at pediatric intensivists from ITx centers; these patients frequently require ICU care at other institutions.. Preoperative management focuses on optimization of organ function, minimizing ventilator-induced lung injury, preventing excessive edema yet maintaining adequate organ perfusion, preventing and controlling sepsis and bleeding from varices at enterocutaneous interfaces, and optimizing nutritional support. The goal is to extend life in stable condition to the point of transplantation. Postoperative care focuses on optimizing perfusion of the mesenteric circulation by maintaining intravascular volume, minimizing hypercoagulability, and providing adequate oxygen delivery. Careful monitoring of the stoma and its output and correction of electrolyte imbalances that may require renal replacement therapy is critical, as are monitoring for and aggressively treating infections, which often present with only subtle clinical clues. Signs of intestinal rejection may be non-specific, and early differentiation from other causes of intestinal dysfunction is important. Understanding of the expanding armamentarium of immunosuppressive agents and their side-effects is required.. As outcomes of ITx improve, transplant teams accept patients with higher pre-operative morbidity and at higher risk for complications. Many ITx patients would benefit from earlier referral for transplant evaluation before severe liver disease, recurrent central venous catheter-related sepsis and venous thromboses develop.

Topics: Child, Preschool; Critical Care; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestines; Liver Transplantation; Pediatrics; Postoperative Care; Postoperative Complications; Preoperative Care; Tacrolimus

Topics: Animals; Antibodies, Monoclonal; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Prognosis; Receptors, Interleukin-2; Tacrolimus; Transplantation Conditioning

Despite the reported high survival with total parenteral nutrition (TPN) therapy for patients with intestinal failure, a considerable number of patients do not escape the potential risks of TPN-associated complications, including hepatic failure, vanishing of central venous access and line sepsis. Thus, intestinal, liver-intestinal and multivisceral transplantation have recently emerged to rescue those who can no longer be maintained on TPN. Before this development, and for nearly three decades, small-bowel transplantation was plagued with uncontrolled rejection, graft v. host disease and fatal infection. These barriers stemmed from the large gut lymphoid mass and heavy microbial load contained in the intestinal lumen. The recent improvement in survival after the clinical introduction of tacrolimus with achievement of full enteric nutritional autonomy qualified the procedure by the US Health Care Financing Administration as the standard of care for patients with intestinal and TPN failure. The decision was supported by a decade of clinical experience with cumulative improvement in patient and graft survival. In addition, the introduction of new effective immunoprophylactic agents and novel therapeutic approaches has contributed to a further increase in the therapeutic advantages of the procedure. The present review article outlines the current clinical practice of intestinal transplantation and defines new management strategies with the aim of raising the level of the procedure to be a better alternative therapy for TPN-dependent patients.

Topics: Contraindications; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Organ Transplantation; Parenteral Nutrition, Total; Patient Selection; Survival Analysis; Tacrolimus; Treatment Outcome

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

Ocular graft-versus-host disease (GVHD) is one of the most severe complications of hematopoietic stem cell transplantation. It manifests as an impairment of the ocular surface, such as severe dry eye disease, and deteriorates the recipient's visual function and quality of life. We encountered an "overlap syndrome" of ocular GVHD, which is characterized by the presence of both acute and chronic GVHD symptoms. In this report, we present the treatment progress of the overlap syndrome in a case with ocular GVHD.. A 57-year-old man with acute myeloblastic leukemia underwent hematopoietic stem cell transplantation. Six weeks after the treatment, the recipient complained of eye pain and discharge. He was diagnosed with the overlap syndrome due to low tear volume, severe corneal epithelitis, hyperemia, and a pseudomembrane on the conjunctiva. Immune cells infiltration, fibrinoid degeneration, fibroblastic and spindle-shaped cells, and fibrosis were observed in the pathology of the pseudomembrane. The recipient was treated with topical immunosuppression and pseudomembrane removal. One week after the initial treatment, ocular GVHD improved. Twelve weeks after the treatment, the topical steroid was discontinued due to the elevation of intraocular pressure.. The assessment of conjunctival pseudomembrane in ocular GVHD is important to determine the stage of the case and to assess systemic GVHD. Furthermore, prompt removal of the pseudomembrane after diagnosis is an appropriate management to reduce the symptoms of ocular GVHD. The combination of topical steroids and immunosuppressive agents is suggested to be an effective treatment in management of overlap syndrome.

Topics: Acute Disease; Betamethasone; Chronic Disease; Conjunctival Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Male; Middle Aged; Ophthalmologic Surgical Procedures; Skin Diseases; Tacrolimus

Topics: Aftercare; Anti-Infective Agents; Biopsy; Brachyspira; Colonoscopy; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Intestinal Diseases; Lupus Erythematosus, Systemic; Medication Therapy Management; Middle Aged; Prednisolone; Radiography, Abdominal; Spirochaetales Infections; Tacrolimus; Tomography, X-Ray Computed

Topics: Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cytarabine; Daunorubicin; Drug Therapy, Combination; Egg Hypersensitivity; Etoposide; Female; Food Hypersensitivity; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Liver Diseases; Male; Middle Aged; Nut Hypersensitivity; Seafood; Tacrolimus; Transplantation Conditioning; Vidarabine

CKD is a frequent long-term complication after SBTx. CNIs are a well-known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC-based maintenance immunosuppression. Median follow-up was seven yr (3-21). A renal biopsy was performed in 14 patients, 1-18 yr post-SBTx. A reduced GFR was observed in 17 children (63%) during the follow-up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post-transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow-up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infant; Intestinal Diseases; Intestine, Small; Male; Renal Insufficiency; Risk Factors; Tacrolimus; Transplantation; Treatment Outcome

Following the introduction of tacrolimus, intestinal transplantation is now a valid option for patients with chronic intestinalfailure. However, its outcome is undermined by the abundant lymphoid component of the graft and the septic nature of the procedure. The heavy immunosuppression necessitated by this transplant, and its non specific nature, creates a risk of infectious and tumoral complications. Several approaches are being tested to improve the immune tolerance of intestinal grafts, both in animals models and in the clinic. The most promising seek to induce specific tolerance while sparing antimicrobial and antitumoral immunity.

Topics: Graft Rejection; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestines; 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

Hydrogen sulfide (H₂S) functions as a neuromodulator, but whether it modulates visceral pain is not well known. This study was designed to determine the role for the endogenous H₂S producing enzyme cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CSE) in a validated rat model of visceral hyperalgesia (VH).. VH was induced by nine-day heterotypic intermittent stress (HIS). Abdominal withdrawal reflex (AWR) scores were determined by measuring the visceromoter responses to colorectal distension (CRD). Dorsal root ganglia (DRG) neurons innervating the colon were labeled by injection of DiI (1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate) into the colon wall. Patch clamp recording techniques were employed to examine excitability and sodium channel currents of colon specific DRG neurons. Tissues from colon related thoracolumbar DRGs were analyzed for CBS, CSE and sodium channel expression.. HIS significantly increased the visceromotor responses to CRD in association with an upregulated expression of CBS not CSE proteins in colon related DRGs. Administration of O-(Carboxymethyl)hydroxylamine hemihydrochloride (AOAA), an inhibitor of CBS, attenuated the AWR scores in HIS-treated rats, in a dose dependent fashion. In contrast, AOAA did not produce any effect on AWR scores in healthy control rats. AOAA reversed the potentiation of sodium channel current densities of colon specific DRG neurons of HIS rats. To further confirm the role for CBS-H₂S signaling, NaHS was used to mimic the production of H₂S by CBS. Application of NaHS significantly enhanced neuronal excitability and potentiated sodium channel current densities of colon DRG neurons from healthy control rats. Furthermore, AOAA reversed the upregulation of Na(V)1.7 and Na(V)1.8 in colon related DRGs of HIS rats.. Our results suggest that upregulation of CBS expression might play an important role in developing VH via sensitization of sodium channels in peripheral nociceptors, thus identifying a specific neurobiological target for the treatment of VH in functional bowel syndromes.

Topics: Animals; Cystathionine beta-Synthase; Enzyme Inhibitors; Hydrogen Sulfide; Hyperalgesia; Intestinal Diseases; Male; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Reflex, Abdominal; Stress, Psychological; Sulfides; Tacrolimus; Up-Regulation; Viscera; Visceral Pain

Intestinal transplantation (ITx) is a life-saving procedure for patients with intestinal failure. The poorer outcome of ITx than of other organ transplantation, however, warrants more clinical and basic research on ITx. Herein, we developed a modified Paul-Mikulicz ileostomy procedure in a swine model of ITx, and investigated its feasibility for obtaining intestinal samples of both the graft and the recipient.. We performed ITx in 10 pairs of piglets, each weighing 15-20 kg. Procurement included an isolated segment of the small bowel, constituting a model of a living, related donor surgery. The recipient procedures included end-to-end anastomosis of vascular stumps, a proximal jejuno-jejunal anastomosis, and a distal modified Paul-Mikulicz ileostomy. The procedure differed from the classic Paul-Mikulicz ileostomy in that a common channel was created in a side-to-side fashion.. Vascular thrombosis occurred in three pigs, resulting in immediate loss of the graft. All other pigs underwent ITx successfully and survived for at least 1 wk (7-180 d). No pig experienced anastomotic leaks, ileus, or stoma-related complications. Moreover, this technique enabled us to obtain tissue samples of both the graft and the native ileum without disturbing the natural bowel conduit.. The modified Paul-Mikulicz ileostomy was feasible in a swine model of ITx. It facilitated the collection of intestinal samples of both the graft and the recipient.

Topics: Animals; Body Weight; Humans; Ileostomy; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Living Donors; Male; Mesenteric Arteries; Mesenteric Veins; Parenteral Nutrition; Postoperative Period; Reperfusion; Swine; Tacrolimus; Transplantation, Homologous

Cyclosporin-A (CsA) and tacrolimus (FK-506) are immunomodulating agents used to prevent rejection in organ transplantation. They are both associated with several side effects, including nephrotoxicity and severe hypertension due to vascular injury, which often appears as a microvascular occlusive disorder (thrombotic microangiopathy, TMA). We report the first case of a microvascular occlusive disorder with the features of TMA in the small bowel of an orthotopic liver transplant (OLT) patient after immunosuppressive therapy with CsA and FK506. The patient presented with severe recurrent abdominal colics and distal subocclusion, requiring aggressive surgical treatment. Histological and ultrastructural analysis of the resected specimen disclosed intestinal TMA. Although rare, such a complication should be considered in the differential diagnosis of abdominal colics in patients undergoing immunosuppressant therapy after OLT.

Topics: Colic; Cyclosporine; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Liver Transplantation; Male; Middle Aged; Purpura, Thrombotic Thrombocytopenic; Tacrolimus

We examined the effect of tacrolimus (FK506), an immunosuppressive drug, on indomethacin-induced small intestinal ulceration in rats. Animals were given indomethacin (10 mg/kg, s.c.), killed 24 h later, and myeloperoxidase (MPO) activity and thiobarbituric acid reactants (TBARS) were evaluated in intestinal lesions. Tacrolimus (0.3 - 3 mg/kg) was administered p.o. twice 0.5 h before and 6 h after indomethacin injection. The expression of inducible nitric oxide synthase (iNOS) mRNA was determined by a TaqMan real-time RT-PCR, while the activity of nuclear factor (NF)-kappaB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA) 6 h after indomethacin treatment. Indomethacin provoked severe hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum, accompanied with increases in MPO activity and TBARS. Oral administration of tacrolimus reduced the severity of indomethacin-induced intestinal lesions in a dose-dependent manner. The increases in MPO activity and TBARS were also significantly attenuated by tacrolimus. The expression of iNOS mRNA was markedly enhanced when examined 6 h after indomethacin administration, and this response was counteracted by tacrolimus. Indomethacin also activated NF-kappaB in a tacrolimus-preventable manner. These results suggest that tacrolimus prevents indomethacin-induced small intestinal ulceration in the rat. This effect may be due to inhibition of iNOS induction through suppression of NF-kappaB activation.

Topics: Animals; Immunosuppressive Agents; Indomethacin; Intestinal Diseases; Lipid Peroxidation; Male; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tacrolimus; Tumor Necrosis Factor-alpha; Ulcer

Autoimmune enteropathy (AIE) is a rare cause of intractable diarrhea in infancy. A variant with onset in adulthood has recently been described. The immune mechanisms underlying AIE are unclear and the experience in the management of adult AIE is very limited.. A 19-year-old male patient with massive refractory diarrhea and significant weight loss was diagnosed with AIE. He did not improve with corticosteroid and azathioprine treatment and was then treated successfully with infliximab. The response to treatment was rapid and complete. Because of a severe life-threatening hypersensitivity reaction during the 4th infliximab dose, infliximab had to be discontinued and therapy with tacrolimus was initiated. A complete clinical remission has since been maintained.. Both infliximab and tacrolimus may provide a therapeutic alternative in patients with adult refractory AIE.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal; Autoimmune Diseases; Biopsy; Drug Therapy, Combination; Endoscopy, Gastrointestinal; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Infusions, Intravenous; Intestinal Diseases; Intestinal Mucosa; Male; Severity of Illness Index; Tacrolimus; Treatment Outcome

Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes.. From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 +/- 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing.. The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation.. Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike.

Topics: Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Child; Child, Preschool; Cyclophosphamide; Cytomegalovirus Infections; Daclizumab; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Male; Organ Transplantation; Survival Analysis; Tacrolimus; Transplantation Conditioning

Modifications in the timing and dosage of immunosuppression can ameliorate the morbidity and mortality that has prevented widespread use of intestinal transplantation (ITx) in children. Thirty-six patients receiving ITx, aged 5 months to 20 years were given 2-3 mg(kg of rabbit anti-thymocyte globulin (rATG, thymoglobulin) just before ITx, and 2-3 mg(kg postoperatively (total 5 mg(kg). Twice daily doses of tacrolimus (TAC) were begun enterally within 24 h after graft reperfusion with reduction of dose quantity or frequency after 3 months. Prednisone or other agents were given to treat breakthrough rejection. After 8-28 months follow-up (mean 15.8 +/- 5.3), 1- and 2-year patient and graft survival is 100% and 94%, respectively. Despite a 44% incidence of acute rejection in the first month, 16 of the 34 (47%) survivors are on TAC (n = 14) or sirolimus (n = 2) monotherapy; 15 receive TAC plus low dose prednisone; one each receive TAC plus sirolimus, TAC plus azathioprine and TAC plus sirolimus and prednisone. There was a low incidence of immunosuppression-related complications. This strategy of immunosuppression minimized maintenance TAC exposure, facilitated the long-term control of rejection, decreased the incidence of opportunistic infections, and resulted in a high rate of patient and graft survival.

Topics: Adolescent; Adult; Animals; Antilymphocyte Serum; Azathioprine; Child; Child, Preschool; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Lymphocyte Depletion; Male; Prednisone; Rabbits; Tacrolimus

In 1996 two transplantation centres in the UK were commissioned by the National Specialist Commissioning Advisory Group for England and Wales to assess small intestinal transplantation in adults. The joint experience of the two centres is presented.. Patients with irreversible small intestinal failure and complications of parenteral nutrition, and those with abdominal disease requiring extensive visceral resection, were assessed as candidates and where appropriate listed for surgery.. Thirty-six patients were assessed for small intestinal transplantation and, of these, 14 underwent surgery. Twelve patients survived the transplantation procedure. Of these, seven patients were alive at 1 year, five at 3 years and three at 5 years. Three patients remain alive. Patient and graft survival improved with experience; the 1-year survival rate improved in the last 4 years of this experience from 43 to 57 per cent, and the 3-year survival rate from 29 to 43 per cent.. Small intestinal transplantation is associated with a high mortality rate but may benefit carefully selected patients in whom conservative management is likely to carry a greater mortality rate.

Topics: Adult; England; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Parenteral Nutrition; Survival Analysis; Tacrolimus; Treatment Outcome; Wales

Autoimmune enteropathy is a life-threatening, chronic disease of the small bowel mucosa, which generally responds well to steroids. Treatment requires long-term immunosuppression, and steroid-sparing treatment strategies are desirable. Azathioprine and cyclosporine A have limitations, however alternatives have not been described in adults.. We present the case of a 54-year-old male patient with autoimmune enteropathy who responded initially to a standard treatment with steroids, but was dependent on 30 mg prednisolone. Medical treatment was changed to tacrolimus after renal function deteriorated under treatment with cyclosporine A. Under this regimen, small bowel histology normalized and the clinical condition is stable after 2 years of introduction of tacrolimus.. This constitutes the first report of effective treatment of adult autoimmune enteropathy with tacrolimus, a substance with a similar mode of action to cyclosporine, but with fewer side effects and improved bioavailability.

Topics: Administration, Oral; Autoimmune Diseases; Duodenum; Humans; Immunosuppressive Agents; Intestinal Diseases; Male; Middle Aged; Tacrolimus

The aim of this study was to determine causes of late graft loss and long-term outcome after isolated intestinal transplantation in children at a single center.. All children who underwent primary isolated intestinal transplantation at our center with a minimum follow-up of 1 year were the subject of this retrospective study.. Twenty-eight children underwent primary isolated intestinal transplantation. Median graft survival was 705 days (range, 0 to 2,630 days) and median patient survival was 1,006 days (range, 0 to 2,630 days). There were 6 deaths and 15 graft losses (including the 6 nonsurvivors). Seven of the losses occurred 6 or more months after transplant. Of these, 2 losses occurred because of death of the recipients of sepsis; both recipients had functioning grafts. The 5 remaining late graft losses occurred because of acute rejection in 2 patients, chronic rejection in 2 (1 with concomitant acute rejection) and a diffuse stricturing process without the histologic hallmarks of chronic rejection in the fifth. All late survivors with intact grafts are off total parenteral nutrition (TPN).. Late graft loss remains a concern in a small percentage of patients after isolated intestinal transplantation. Nutritional autonomy from TPN is possible in the majority of these children after transplantation.

Topics: Age Factors; Child; Child, Preschool; Cyclosporine; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestine, Small; Intestines; Parenteral Nutrition, Total; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Autoimmune Diseases; Chronic Disease; Diarrhea; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infant; Infliximab; Intestinal Diseases; Male; Parenteral Nutrition; Tacrolimus

Topics: Biopsy; Consanguinity; Female; Humans; Ileostomy; Immunosuppressive Agents; Infant, Newborn; Intestinal Diseases; Intestine, Small; Intestines; Liver Transplantation; Microscopy, Electron; Microvilli; Prednisolone; Tacrolimus; Treatment Outcome

Successful small bowel transplantation requires effective immunosuppression that preserves intestinal function but avoids opportunistic infection. This study aims to evaluate FK506 as a single immunosuppressant in different pretreatment regimens in a rat high responder strain combination.. Lewis --> DA rat heterotopic small bowel transplantation was performed. Studied groups were (1) untreated control, n = 12; (2) FK-1, n = 8; (3) FK-3, n = 8. FK506 (2 mg/kg/d, intramuscularly) was given to the recipients for 1 day (FK-1) and 3 days (FK-3) before small bowel transplantation, followed by 2 weeks of subtherapeutic treatment (0.3 mg/kg/d, intramuscularly) after small bowel transplantation. Syngeneic small bowel transplantation also was performed (n = 8). FK blood levels, maltose absorption test, histology, and bacteriology were performed at different postoperative days.. Allograft survival was prolonged significantly with FK pretreatment, being more so in FK-3 group (FK-1, 22.2 +/- 1.5 d; FK-3, 40.7 +/- 14.1 d; control, 6.6 +/- 0.8 d; P< .01). In the first postoperative week, FK blood level was significantly higher in FK-3 group (19.8 +/- 1.5 ng/mL) than in FK-1 group (5.0 +/- 0.4 ng/mL; P < .05). There was no evidence of systemic infection in either FK-treated group. For maltose absorption, control allograft was abnormal on day 7 correlating to severely damaged intestinal architecture. In contrast, FK-treated allografts showed well-protected intestinal structure and normal absorption on days 7 and 21.. High FK506 blood levels in the first postoperative week, achieved with FK pretreatment, prolonged intestinal allograft survival and preserved intestinal structure and function without allowing systemic infection.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Intestinal Diseases; Intestine, Small; Male; Postoperative Complications; Postoperative Period; Preoperative Care; Probability; Rats; Rats, Inbred Lew; Sensitivity and Specificity; Tacrolimus; Tissue Transplantation; Transplantation Immunology; Transplantation, Homologous; Treatment Outcome

Graft-versus-host disease (GvHD) is a multi-organ disease caused by mature donor T cells that are activated by alloantigens expressed by the host antigen-presenting cells. GvHD has been reported after solid organ transplantation with two principal presentations: humoral and cellular. In the cellular type of GvHD after liver transplantation the symptoms are identical to the GvHD after bone marrow transplant, except that the liver is spared because it lacks host antigens. We have described three cases of intestinal GvHD after pediatric liver transplant with an unusual recurrent late presentation in two patients. Two patients were female, and their age at the time of transplant was 8 and 9 months, respectively, and one was an 8-month-old male. They all received reduced liver allografts of identical blood type from three different donors. One patient received two doses of donor bone marrow cell infusion. Two patients received double immunosuppressive therapy constituted by tacrolimus at a dose of 0.05 mg/kg p.o. b.i.d. and steroids 10 mg p.o. daily. One patient received a triple drug immunosuppression with tacrolimus (0.05 mg/kg p.o. b.i.d.), steroids (10 mg p.o. daily) and mycophenolate mofetil (125 mg p.o. b.i.d.). Diagnosis of intestinal GvHD was confirmed histologically on intestinal biopsies performed at the time of presentation of the clinical symptoms or at autopsy.

Topics: Adolescent; Adrenal Cortex Hormones; Biopsy; Bone Marrow Transplantation; Child; Colon; Colon, Sigmoid; Duodenum; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Liver Transplantation; Male; Mycophenolic Acid; Recurrence; Tacrolimus; Time Factors; Tissue Donors

A case of X-linked autoimmune enteropathy was successfully treated with cyclosporine A (CsA) or tacrolimus (FK506) and developed extremely high serum levels of IgE during the immunosuppressive therapy. Serum IgE levels increased from 190 to 1,000-2,500 IU/ml with CsA therapy and as high as 80,000 IU/ml with subsequent FK506 therapy. Serum IgG2 and IgG4 levels were slightly elevated compared to serum IgE levels. Thereafter, serum IgE levels progressively decreased in parallel with a reduced dosage of FK506. Total serum IgG levels and peripheral eosinophil counts, however, showed no significant changes during the course. These observations suggest that both CsA and FK506, potent immunosuppressants, could paradoxically enhance some immune responses, possibly through the action of CsA-/FK506-resistant immune systems.

Topics: Anemia, Hemolytic; Child; Cyclosporine; Humans; Immunoglobulin E; Intestinal Diseases; Male; Polyendocrinopathies, Autoimmune; Tacrolimus

Topics: Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Tacrolimus

Thirty-seven patients were listed for small bowel transplantation; 16 were transplanted and 15 died while waiting for a donor. Cyclosporine (N = 6) or tacrolimus (N = 10) were used for immune suppression. Graft rejection rates were lower in the combined liver/small bowel grafts than the isolated intestinal transplants (1/7 vs 5/7; P < 0.01) All of the cyclosporine group have died; the median survival was 25.7 months with two patients living more than five years. The tacrolimus group had fewer infections and a shorter hospital stay. All but two are alive with a median survival of 13 months. Seven of eight long-term survivors are off intravenous feedings. We conclude that small bowel transplantation is a life-saving option for patients with intestinal failure who cannot be maintained on total parenteral nutrition.

Topics: Adolescent; Adult; Child; Child, Preschool; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestine, Small; Liver Failure; Liver Transplantation; Male; Middle Aged; Postoperative Care; Tacrolimus; Tissue Donors

Autoimmune enteropathy is characterized by chronic secretory diarrhea, villous atrophy, associated autoantibodies, and a partial response to immunosuppression. Currently available therapy (including steroids and cyclosporine) has resulted in remission only in a subset of patients. We evaluated the effects of tacrolimus (FK506) in patients with autoimmune enteropathy refractory to steroids and cyclosporine. Three patients with diagnosed autoimmune enteropathy who continued to have intractable diarrhea despite treatment with steroids and/or cyclosporine were treated with oral tacrolimus. Despite documented histological villous atrophy and poor absorption of oral cyclosporine, therapeutic tacrolimus levels were easily achieved in all 3 patients. All patients showed clinical improvement as documented by decreased stool output and ability to be weaned off parenteral nutrition; response time ranged from 1 to 4 months after tacrolimus was begun. Histological improvement was noted in all patients, and the small bowel biopsy specimens of 2 of the 3 patients showed a return to normal. All patients have been followed up for at least 6 months and are in clinical remission; 1 has received a bone marrow transplant for underlying immunodeficiency. Tacrolimus is a useful drug in the treatment of autoimmune enteropathy, even in patients who have not responded to steroids or cyclosporine. No long-term follow-up of patients with autoimmune enteropathy treated with tacrolimus is currently available.

Topics: Administration, Oral; Atrophy; Autoimmune Diseases; Biopsy; Duodenum; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Male; Remission Induction; Tacrolimus

Topics: Biopsy; Diarrhea, Infantile; Humans; Immunosuppressive Agents; Infant, Newborn; Intestinal Diseases; Intestinal Mucosa; Intestines; Liver Transplantation; Male; Microscopy, Electron; Microvilli; Parenteral Nutrition, Total; Tacrolimus

Topics: Autoimmune Diseases; Betamethasone; Child, Preschool; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Genetic Linkage; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Male; Sex Chromosome Aberrations; Tacrolimus; X Chromosome

After the successful evolution of hepatic transplantation during the last decade, small bowel and multivisceral transplantation remains the sole elusive achievement for the next era of transplant surgeons. Until recently, and for the last thirty years, the results of the sporadic attempts of intestinal transplantation worldwide were discouraging because of unsatisfactory graft and patient survival. The experimental and clinical demonstration of the superior therapeutic efficacy of FK 506, a new immunosuppressive drug, ushered in the current era of small bowel and multivisceral transplantation with initial promising results.. Forty-three consecutive patients with short bowel syndrome, intestinal insufficiency, or malignant tumors with or without associated liver disease, were given intestinal (n = 15), hepatic and intestinal (n = 21), or multivisceral allografts that contained four or more organs (n = 7). Treatment was with FK 506 based immunosuppression. The ascending and right transverse colon were included with the small intestine in 13 of the 43 grafts, almost evenly distributed between the three groups.. After six to 39 months, 30 of the 43 patients are alive, 29 bearing grafts. The most rapid convalescence and resumption of diet, as well as the highest three month patient survival (100 percent) and graft survival (88 percent) were with the isolated intestinal procedure. However, this advantage was slowly eroded during the first two postoperative years, in part because the isolated intestine was more prone to rejection. By the end of this time, the best survival rate (86 percent) was with the multivisceral procedure. With all three operations, most of the patients were able to resume diet and discontinue parenteral alimentation, and in the best instances, the quality of life approached normal. However, the surveillance and intensity of care required for these patients for the first year, and in most instances thereafter, was very high, being far more than required for patients having transplants of the liver, kidney or heart.. Although intestinal transplantation has gone through the feasibility phase, strategies will be required to increase its practicality. One possibility is to combine intestinal transplantation with contemporaneous autologous bone marrow transplantation.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Intestinal Diseases; Intestines; Liver Transplantation; Male; Middle Aged; Organ Transplantation; Quality of Life; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome; Viscera