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      Changes in the Small Bowel of Symptomatic Kidney Transplant Recipients Converted from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium

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          Abstract

          Background/Aims: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium ( EC-MPS) given to treat GI mucosal lesions. Methods: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE. Results: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms. Conclusion: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.

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          Most cited references23

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          Small bowel mucosal injury is reduced in healthy subjects treated with celecoxib compared with ibuprofen plus omeprazole, as assessed by video capsule endoscopy.

          Small bowel mucosal injury associated with non-selective non-steroidal anti-inflammatory drugs is being increasingly recognized. To evaluate the incidence of small bowel injury in healthy subjects receiving celecoxib or ibuprofen plus omeprazole using video capsule endoscopy (VCE). Subjects with normal baseline VCE were randomly assigned to receive celecoxib 200 mg b.d., ibuprofen 800 mg t.d.s. plus omeprazole 20 mg o.d. or placebo for 2 weeks. The primary end point was mean number of small bowel mucosal breaks per subject. Secondary end points included correlation of faecal calprotectin levels with the primary outcome. After treatment, the mean number of small bowel mucosal breaks per subject and the percentage of subjects with mucosal breaks were 0.7/25.9% for ibuprofen/omeprazole compared with 0.2/6.4% for celecoxib and 0.1/7.1% placebo (both comparisons P < 0.001). There were no significant differences between celecoxib and placebo in any measure. Mean increases in faecal calprotectin levels were higher in subjects receiving ibuprofen/omeprazole compared with celecoxib (P < 0.001), but no correlation was determined between these levels and small bowel mucosal breaks. Among healthy subjects with no baseline endoscopic lesions, celecoxib was associated with significantly fewer small bowel mucosal breaks than ibuprofen/omeprazole as assessed by VCE.
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            A randomized trial comparing wireless capsule endoscopy with push enteroscopy for the detection of small-bowel lesions.

            Wireless capsule endoscopy is a new, painless method of imaging the entire small bowel. It has not been compared with push enteroscopy. We compared the sensitivity, specificity, and safety of capsule and push enteroscopy in detecting small-bowel lesions. Nine to 13 radiopaque, colored beads (3-6 mm diameter) were sewn in random order inside 9 canine small bowels, half within the first meter, and confirmed on x-ray. After recovery, the number, order, and color of beads were assessed in 23 capsule enteroscopies and 9 push enteroscopies in a random order. The surgeons, push enteroscopists, capsule video interpreters, and pathologist were blinded to the others' findings. The capsules identified more beads than push enteroscopy (median, 6 [range, 2-9] vs. 3 [range, 2-6 beads]; P < 0.001). The sensitivity of the capsule was 64% compared with 37% for push enteroscopy. The specificity was 92% for capsule enteroscopy and 97% for push enteroscopy. The capsules identified significantly more beads beyond the reach of the push enteroscope (median, 4 [range, 2-7] vs. 0; P < 0.0001). Hair, ingested plastic, ulceration, submucosal swelling, and worms were clearly identified by the capsule. The capsules passed safely through the animals with no significant histologic findings. Wireless capsule endoscopy detected more abnormalities in the small bowel than push enteroscopy.
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              Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes.

              Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug used in the management of transplant recipients. Although gastrointestinal (GI) toxicity is a known complication of MMF, the literature characterizing the pathologic features of MMF in the GI tract is sparse. This study characterizes the pathologic features of MMF toxicity in both the upper and lower GI tract, correlating it with clinical and endoscopic findings. Seventy-five GI biopsies (9 esophageal, 15 gastric, 16 duodenal, 5 ileal, 30 colonic) from 46 transplant recipients from 2002 to 2006 were obtained and assessed for multiple histologic features. Clinical features were recorded for all cases and endoscopic findings. Only MMF patients showed ulcerative esophagitis (5/7 cases) and reactive gastropathy (4/10 cases). Only MMF patients showed graft-versus-host disease (GVHD)-like features in duodenal (4/12 cases) and ileal (1/5 cases) biopsies. GVHD-like changes were seen more frequently among patients on MMF compared with those not on MMF [9 (56%) vs. 2 (14%); P=0.017]. Crypt architectural disarray [12 (75%) vs. 2 (14%); P=0.001], lamina propria edema [9 (56%) vs. 2 (14%); P=0.017], increased lamina propria inflammation [13 (81%) vs. 3 (21%); P=0.001], dilated damaged crypts [7 (44%) vs. 1 (7%); P=0.024], and increased crypt epithelial apoptosis [9 (56%) vs. 2 (14%); P=0.017] were more common with MMF patients compared with non-MMF patients. In conclusion, pathologists should be aware of the potential manifestations of MMF toxicity throughout the GI tract, including ulcerative esophagitis, reactive gastropathy, and GVHD-like features in intestinal biopsies.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2014
                September 2014
                02 September 2014
                : 40
                : 2
                : 184-190
                Affiliations
                aDepartment of Medicine, David Geffen School of Medicine, UCLA and bDivision of Digestive Diseases Cedars-Sinai Medical Center, Los Angeles, Calif., USA
                Author notes
                *Suphamai Bunnapradist, 1033 Gayley Ave., suite 208, Los Angeles, CA 90024 (USA), E-Mail bunnapradist@mednet.ucla.edu
                Article
                365360 Am J Nephrol 2014;40:184-190
                10.1159/000365360
                25196230
                3e265b13-b9dd-4ed8-bfab-66eef0d1e4e6
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 08 April 2014
                : 11 June 2014
                Page count
                Tables: 2, Pages: 7
                Categories
                Original Report: Transplantation

                Cardiovascular Medicine,Nephrology
                Mycophenolate sodium,Gastrointestinal,Capsule endoscopy,Mycophenolate mofetil,Small bowel

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