Induction therapy reduces the frequency of acute rejection and delayed graft function after transplantation. A rabbit antithymocyte polyclonal antibody or basiliximab, an interleukin-2 receptor ...monoclonal antibody, is most commonly used for induction.
In this prospective, randomized, international study, we compared short courses of antithymocyte globulin and basiliximab in patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor. Patients taking cyclosporine, mycophenolate mofetil, and prednisone were randomly assigned to receive either rabbit antithymocyte globulin (1.5 mg per kilogram of body weight daily, 141 patients) during transplantation (day 0) and on days 1 through 4 or basiliximab (20 mg, 137 patients) on days 0 and 4. The primary end point was a composite of acute rejection, delayed graft function, graft loss, and death.
At 12 months, the incidence of the composite end point was similar in the two groups (P=0.34). The antithymocyte globulin group, as compared with the basiliximab group, had lower incidences of acute rejection (15.6% vs. 25.5%, P=0.02) and of acute rejection that required treatment with antibody (1.4% vs. 8.0%, P=0.005). The antithymocyte globulin group and the basiliximab group had similar incidences of graft loss (9.2% and 10.2%, respectively), delayed graft function (40.4% and 44.5%), and death (4.3% and 4.4%). Though the incidences of all adverse events, serious adverse events, and cancers were also similar between the two groups, patients receiving antithymocyte globulin had a greater incidence of infection (85.8% vs. 75.2%, P=0.03) but a lower incidence of cytomegalovirus disease (7.8% vs. 17.5%, P=0.02).
Among patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor, induction therapy consisting of a 5-day course of antithymocyte globulin, as compared with basiliximab, reduced the incidence and severity of acute rejection but not the incidence of delayed graft function. Patient and graft survival were similar in the two groups. (ClinicalTrials.gov number, NCT00235300 ClinicalTrials.gov.).
Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in ...the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn's disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study's results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.
Secondary Authors
Vincent T. Armenti, MD, PhD, Professor of Surgery, Temple University School of Medicine, Abdominal Transplant Program, Philadelphia, Pennsylvania
Phyllis August, MD, MPH, Professor ...of Medicine, Division of Hypertension, Weill Medical College of Cornell University, New York, New York
Lisa A. Coscia, RN, BSN, CCTC, Research Coordinator, National Transplantation Pregnancy Registry, Temple University School of Medicine, Philadelphia, Pennsylvania
Connie L. Davis, MD, Professor of Medicine, Div. of Nephrology, Univ. of Washington, Box 356174, 1959 NE Pacific St., Seattle, WA 98195
John M Davison MD, Professor of Obstetric Medicine, Consultant Obstetrician, University of Newcastle upon Tyne, School of Surgical and Reproductive Sciences, Faculty of Medical Sciences, William Leech Building, Newcastle upon Tyne NE2 4HH, UK
Thomas Easterling, MD, Professor, Maternal Fetal Medicine, University of Washington, Box 356460, 1959 ND Pacific Street, Seattle, WA 98195
Jan M. Friedman, MD, PhD, Professor of Medical Genetics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
Susan Hou, MD, Professor of Medicine, Department of Medicine, Loyola University Medical Center, Maywood, IL
Janet Karlix, Pharm, D, FCCP, Associate Professor, College of Pharmacy, University of Florida, Gainesville, FL
Kathleen D, Lake, Pharm.D., BCPS, FCCP, Adjunct Professor, University of Michigan Medical School and College of Pharmacy, Ann Arbor, MI, Medical Transplant Liaison, Roche Laboratories, Nutley, NJ
Marshall Lindheimer, MD, Professor Emeritus, Departments of Obstetrics & Gynecology, and Medicine,, University of Chicago, Chicago, Ill
Arthur J. Matas, MD, Professor of Surgery, University of Minnesota, Department of Surgery, University of Minnesota Hospital, Minneapolis, MN
Michael J. Moritz, MD, Professor of Surgery, Drexel University College of Medicine, Director, Abdominal Transplantation, Hahnemann University Hospital, Philadelphia, Pennsylvania
Caroline A. Riely, MD, Professor, Medicine and Pediatrics, Chief of Hepatology Section, Gastroenterology Division, University of Tennessee Science Center
Lainie Friedman Ross, MD, PhD, Associate Director, MacLean Center for Clinical Medical Ethics, Associate Professor, University of Chicago, Department of Pediatrics, Chicago, Illinois
James R. Scott, MD, Professor and Chair Emeritus, Department of Obstetrics and Gynecology, University of Utah Medical Center, Salt Lake City, Utah
Lynne E. Wagoner, MD, Director, Heart Failure and Transplantation, Associate Professor, Division of Cardiology, University of Cincinnati, Cincinnati, Ohio
Lucile Wrenshall, MD, PhD, Associate Professor, Department of Surgery, Division of Transplantation, University of Nebraska Medical Center, Omaha, NE
And the consensus committee organizers of the Women's Health Committee of the American Society of Transplantation:
Patricia L. Adams, MD, Professor of Medicine, Associate Dean for Student Services, Wake Forest University School of Medicine, Med Center Blvd, Winston Salem, NC 27157
Ginny L. Bumgardner MD, PhD, Associate Professor of Surgery, Division of Transplantation, The Ohio State University Med. Center, Columbus, Ohio
Richard N. Fine, MD, Professor and Chairman, State U. of NY, Health Science Centre T‐11 020, Stony Brook, NY 11794–8111
Simin Goral, MD, Associate Professor of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania Health System, Philadelphia, Pennsylvania
Sheri M. Krams, PhD, Associate Professor, Department of Surgery/Transplant, Stanford University School of Medicine, 1201 Welch Road, MSLS P313, Stanford, CA 94305–5492
Olivia M. Martinez, PhD, Associate Professor, Stanford University School of Medicine, Dept of Surgery, 1201 Welch Road, MSLS P312, Stanford, CA 94305–5492
Nina Tolkoff‐Rubin, MD, Director of Hemodialysis and CAPD Units, Medical Director for Renal Transplantation, Massachusetts General Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts
Martha Pavlakis, MD, Assistant Professor of Medicine, Harvard Medical School, Medical Director, Kidney and Pancreas Transplantation, Beth Israel Deaconess Medical Center, The Transplant Center LMOB 7th floor, 110 Francis Street, Boston, MA 02215
Velma Scantlebury, MD, Professor of Surgery, Chief, Division of Transplantation, Assistant Dean for Community Education, University of South Alabama, 2451 Fillingim Street, 10th Flr, Suite F, Mobile, Alabama
It has been almost 50 years since the first child was born to a female transplant recipient. Since that time pregnancy has become common after transplantation, but physicians have been left to rely on case reports, small series and data from voluntary registries to guide the care of their patients. Many uncertainties exist including the risks that pregnancy presents to the graft, the patient herself, and the long‐term risks to the fetus. It is also unclear how to best modify immunosuppressive agents or treat rejection during pregnancy, especially in light of newer agents available where pregnancy safety has not been established.
To begin to address uncertainties and define clinical practice guidelines for the transplant physician and obstetrical caregivers, a consensus conference was held in Bethesda, Md. The conferees summarized both what is known and important gaps in our knowledge. They also identified key areas of agreement, and posed a number of critical questions, the resolution of which is necessary in order to establish evidence‐based guidelines. The manuscript summarizes the deliberations and conclusions of the conference as well as specific recommendations based on current knowledge in the field.
Binge eating disorder (BED) is associated with obesity. Zonisamide is a novel antiepileptic drug associated with weight loss. The purpose of this study was to evaluate zonisa-mide in the treatment of ...BED associated with obesity.
In this 16-week, single-center, randomized, double-blind, placebo-controlled, flexible-dose (100-600 mg/day) trial, 60 outpatients with DSM-IV-TR BED received zonisamide (N = 30) or placebo (N = 30). The primary outcome measure was weekly frequency of binge eating episodes. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 5, 2003, through October 1, 2004.
Compared with placebo, zonisamide was associated with a significantly greater rate of reduction in binge eating episode frequency (p = .021), body weight (p < .001), BMI (p = .001), and scores on the Clinical Global Impressions-Severity scale (p < .001), Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (p < .001), and Three Factor Eating Questionnaire disinhibition scales (p < .001). Plasma ghrelin concentrations increased with zonisamide but decreased with placebo (p = .001). The mean (SD) zonisamide daily dose at endpoint evaluation was 436 (159) mg/day. Twelve patients (N = 8 receiving zonisamide, N = 4 receiving placebo) discontinued because of adverse events. The most common reasons for discontinuing zonisamide were accidental injury with bone fracture (N = 2), psychological complaints (N = 2), and cognitive complaints (N = 2).
Zonisamide was efficacious, but not well tolerated, in the short-term treatment of BED associated with obesity.
ClinicalTrials.gov identifier NCT00221442.
Binge-eating disorder (BED) is associated with obesity. Atomoxetine is a highly selective norepinephrine reuptake inhibitor associated with weight loss. The purpose of this study was to evaluate ...atomoxetine in the treatment of BED.
In this 10-week, single-center, randomized, double-blind, placebo-controlled, flexible dose (40-120 mg/day) trial, outpatients with DSM-IV-TR BED received atomoxetine or placebo. The primary outcome measure was binge-eating episode frequency. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 2004 through October 2005.
Compared with placebo (N = 20), atomoxetine (N = 20) was associated with a significantly greater rate of reduction in binge-eating episode frequency, as well as in binge day frequency, weight, body mass index, and scores on the Clinical Global Impressions-Severity of Illness scale, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating obsession sub-scale, and Three Factor Eating Questionnaire hunger subscale. The mean (SD) atomoxetine daily dose at endpoint evaluation was 106 (21) mg/day. Four patients (N = 3 receiving atomoxe-tine, N = 1 receiving placebo) discontinued because of adverse events. The reasons for atomoxetine discontinuation were increased depressive symptoms (N = 1), constipation (N = 1), and nervousness (N = 1).
Atomoxetine was efficacious and fairly well tolerated in the short-term treatment of BED.
ClinicalTrials.gov identifier NCT00327834.
The authors' goal was to assess the efficacy of sertraline in the treatment of binge eating disorder.
Thirty-four outpatients with DSM-IV binge eating disorder were randomly assigned to receive ...either sertraline (N=18) or placebo (N=16) in a 6-week, double-blind, flexible-dose (50-200 mg) study. Except for response level, outcome measures were analyzed by random regression methods, with treatment-by-time interaction as the effect measure.
Compared with placebo, sertraline was associated with a significantly greater rate of reduction in the frequency of binges, clinical global severity, and body mass index as well as a significantly greater rate of increase in clinical global improvement. Patients receiving sertraline who completed the study demonstrated a higher level of response, although the effect was not significant.
In a 6-week trial, sertraline was effective and well tolerated in the treatment of binge eating disorder.
Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are ...heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.
The rate of mycophenolic acid (MPA) absorption after oral administration of mycophenolate mofetil (MMF) is delayed in patients with diabetes. Cyclosporine (CsA) decreases MPA exposure by inhibiting ...enterohepatic recirculation of MPA/MPA glucuronide, and tacrolimus (TRL) may alter the rate and extent of MPA absorption due to its prokinetic properties especially in patients with diabetic gastroparesis. This study evaluated the effect of changing from CsA to TRL on pharmacokinetics of MPA in stable renal transplant recipients with long-standing diabetes. Eight patients were switched from a stable dose of CsA to TRL while taking MMF 1 g twice daily. The 12-hour steady-state total plasma concentration-time profiles of MPA and MPA glucuronide were obtained after oral administration of MMF on 2 occasions: first while taking CsA and second after changing to TRL. Pharmacokinetic parameters of MPA were calculated by the noncompartmental method. Changing from CsA to TRL resulted in significantly increased MPA exposure (area under the concentration-time curve from 0 to 12 hours, AUC0-12) by 46 +/- 32% (P = 0.012) and MPA predose concentration (C0) by 121 +/- 67% (P = 0.008). The magnitude of change in MPA exposure did not correlate well with MPA-C0 or CsA trough concentration. Switching to TRL had minimal impact on peak concentration of MPA (15.0 +/- 6.9 mg/L with CsA versus 16.1 +/- 9.7 mg/L with TRL, P = 0.773) and time to reach the peak concentration (1.0 +/- 0.4 hours with CsA versus 1.2 +/- 0.8 hours with TRL, P = 0.461). Highly variable and unpredictable changes in MPA exposure among renal transplant patients with diabetes do not support a strategy of preemptively adjusting MMF dose when switching calcineurin inhibitors in this population.
Study Objectives. To determine if coadministration of polysaccharide iron complex and slow‐release ferrous sulfate alter the absorption of mycophenolic acid (MPA), and to examine the potential ...influence of dosing relative to mycophenolate mofetil (MMF) administration and the effect of immediate‐ versus sustained‐release iron products on the steady‐state pharmacokinetics of MPA.
Design. Prospective, open‐label, three‐phase, crossover, steady‐state pharmacokinetic study.
Setting. National Institutes of Health–sponsored General Clinical Research Center at a university medical center.
Patients. Twelve adult (mean age 50 yrs) renal transplant recipients who were receiving concomitant iron and MMF maintenance therapy.
Intervention. Oral iron therapy was coadministered with MMF on days −6–0, MMF was administered alone on days 1–8 (control phase), then oral iron therapy was administered 2 hours after MMF administration on days 9–16.
Measurements and Main Results. Baseline demographics, concurrent drug regimens, and clinical laboratory values were assessed. Blood samples were obtained at baseline and at 1, 2, 3, 4, 6, 8, and 12 hours after MMF administration on days 0, 8, and 16. The MPA levels were measured by high‐performance liquid chromatography. We found no significant differences in the dose‐standardized area under the concentration‐time curve from 0–12 hours (AUC0–12) for MPA between the control phase (39.66 ± 8.70 mg•hr/L) and the concomitant ferrous sulfate or dose‐separated ferrous sulfate (37.56 ± 9.95 or 32.84 ± 8.43 mg•hr/L, respectively, p>0.05) phases. Dose‐standardized AUC0–12 values for MPA did not significantly differ after the concomitant administration of polysaccharide iron complex from that of the control phase (48.46 ± 9.68 and 43.80 ± 9.46 mg•hr/L, respectively, p=0.065). However, the AUC0–12 for MPA significantly increased when polysaccharide iron complex was administered 2 hours after MMF (53.41 ± 11.75 mg•hr/L, p=0.012). Maximum concentrations and times to reach maximum concentrations remained consistent across all study phases in each arm of the trial (p>0.05).
Conclusion. Multiple doses of iron therapy—slow‐release ferrous sulfate, or polysaccharide iron complex—did not significantly reduce systemic exposure to MMF, as measured by using AUC0–12 values.
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