Clostridium difficile disease in solid organ transplant recipients: a recommended treatment paradigm.

PURPOSE OF REVIEW: Organ transplant recipients have an increased incidence of Clostridium difficile disease and lower clinical response rates compared with the general population. Transplant specific treatment approaches are not defined. Therefore, a review of therapeutics in the transplant population is needed. RECENT FINDINGS: A literature review on the current therapies for C. difficile was performed focusing on the evidence in transplant recipients and immunosuppressed populations. SUMMARY: Transplant patients warrant an aggressive approach to treatment. The authors propose a suggested treatment paradigm for therapy.

Cytokine-targeted therapy for the management of solid organ transplant recipients.

INTRODUCTION: The number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects. BODY: Cytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn's, and multiple sclerosis. CONCLUSION: This article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.

Insights From Practice With Use of Direct Oral Anticoagulants in Transplantation.

Solid organ transplant patients are at risk of developing atrial fibrillation and venous thromboembolism. Direct oral anticoagulants are considered an attractive option for anticoagulation in patients due to their convenience; however, strong evidence of their use in transplantation is lacking. We conducted a search using Pubmed, Embase, and Scopus databases, in addition to International Society of Heart and Lung transplantation and American Transplant Congress abstracts (from 2012 through December 2017). Fourteen articles were reviewed that included case reports, retrospective case series, or chart review analyses of small cohorts. Based on this review, the findings can only generate hypotheses that should be further studied in a larger randomized cohort. This review can help clinicians gain insight into the use of direct oral anticoagulant in this special population. For now, clinicians should be cautious about their use in this special population.

Marijuana Use and Organ Transplantation: a Review and Implications for Clinical Practice.

PURPOSE OF REVIEW: Physicians of all disciplines must rapidly adjust their clinical practices following the expansion of marijuana legalization across the country. Organ transplantation teams are uniquely struggling in this gray zone with eight states having passed laws explicitly banning the denial of transplant listing based on a patient's use of medical marijuana. In this review, we examine the clinical evidence of marijuana use in transplant patients to enable psychiatric providers to meaningfully contribute to the relevant medical and psychiatric aspects of this issue in a unique patient population. RECENT FINDINGS: There is no consensus among experts regarding marijuana use in transplantation patients. There are extant case reports of post-transplant complications attributed to marijuana use including membranous glomerulonephritis, ventricular tachycardia, and tacrolimus toxicity. However, recent studies suggest that the overall survival rates in kidney, liver, lung, and heart transplant patients using marijuana are equivalent to non-users. Transplant teams should not de facto exclude marijuana users from transplant listing but instead holistically evaluate a patient's candidacy, integrating meaningful medical, psychiatric, and social variables into the complex decision-making process. Psychiatric providers can play a key role in this process. Appropriate stewardship over donor organs, a limited and precious resource, will require a balance of high-clinical standards with inclusive efforts to treat as many patients as possible.

EDTA Treatment of Serum Unmasks Complement-Mediated Prozone Inhibition in Human Leukocyte Antigen Antibody Testing.

OBJECTIVES: Luminex-based single-antigen bead human leukocyte antigen (HLA) antibody testing is widely used to define HLA antibodies for transplant compatibility. False-negative results can occur with complement-mediated prozone inhibition. This study assessed the effect of EDTA on the assay background reactivity and fluctuations in antibody mean fluorescent intensity. METHODS: Serum specimens were retrospectively tested using Luminex-based single-antigen beads with and without EDTA. Treated and untreated serum samples were compared by two measures: changes in background reactivity and changes in HLA antibody strength after EDTA treatment. RESULTS: Ten pretransplant and 48 posttransplant specimens were identified: lung (22), heart (10), kidney (21), heart/lung (two), pancreas (one), small bowel (one), and liver (one). After EDTA treatment, weak antibodies (below 2,000 mean florescent intensity) demonstrated the largest fluctuations. Newly identified HLA antibodies were seen in 16% (8/49) of class I and 26% (15/57) of class II beads. EDTA treatment did not result in false-negative reactions compared with untreated serum. CONCLUSIONS: EDTA serum pretreatment mitigated complement-mediated prozone inhibition and improved accurate HLA antibody detection. The background reactivity and the false-negative rate of the assay appear unchanged.

Is Tracheal Transplantation Possible With Cryopreserved Tracheal Allograft and Hyperbaric Oxygen Therapy? An Experimental Study.

BACKGROUND: Allografts have achieved prominence for tracheal reconstruction because of their natural physiologic and anatomic structure, which preserves respiratory tract flexibility and lumen patency. The immunomodulatory effects of cryopreservation prevent tracheal allograft rejection. In addition, hyperbaric oxygen therapy (HBOT) accelerates wound healing by promoting epithelization and neovascularization. This experimental study investigated the early and late effects of HBOT on cryopreserved tracheal allografts (CTAs). METHODS: The study used 33 outbred Wistar rats weighing 300 to 350 g as allograft transplantation donors and recipients. Among these, 22 recipient rats were randomly assigned to the HBOT (n = 11) and control (n = 11) groups. Rats in the HBOT group were treated with 100% oxygen for 60 minutes at 2.5 atmospheres of absolute pressure for 7 days. Recipient rats in both groups were euthanized at 1 week (n = 5) and 4 weeks (n = 6) after transplantation, defined as the early and late periods, respectively. RESULTS: In the early period, no significant histopathologic differences were observed between groups (p > 0.05). However, microscopic evaluation of the control group during the late period showed low epithelization of the CTA. In contrast, microscopic evaluation of the HBOT group during this same period revealed epithelium covering the transplanted CTA lumen. Significant epithelization and vascularization and significantly reduced inflammation and fibrosis were found in the HBOT group compared with the control group (p < 0.05). CONCLUSIONS: HBOT may be effective in tracheal reconstruction by increasing epithelization and neovascularization after extended tracheal resection. HBOT, therefore, should be considered in CTA transplantation.

Organ Donation From Deceased Donors: A Proactive Detection Program in Saudi Arabia.

Several challenging obstacles remain to increasing the number of organ donations from deceased patients in a hospital setting. These include medical, administrative, and ethical issues. Possible medical obstacles include the failure of early recognition of possible donors and inadequate care of potential and actual donors. To maximize the use of donated organs, proper care of the donors and expedited donor consent cannot be overemphasized. The care rendered to patients should ensure appropriate perfusion and nutrition of the organs, with meticulous follow-up until organ recovery. For example, patients involved in accidents are presumed to be healthy, but many have no available medical history on file. At the time of organ recovery, unexpected infections or malignancies can be minimized by raising the index of suspicion of the presence of serious conditions in donors, especially in donors with unknown medical history. A careful physical examination and an appropriate and aggressive laboratory investigation may disclose the cause of suspected clinical conditions in these potential donors. Individuals who work in intensive care units are the main group of health care providers directly involved in the process of organ donation. Appointing a donor coordinator in each intensive care unit could improve all aspects of organ donation. Such coordination could harmonize efforts toward the goals mentioned above and surmount the obstacles encountered during deceased-donor organ donation. Here, we describe the preliminary results of the Proactive Detection Program, a collaboration between the Saudi Center for Organ Transplantation (the national organ donation and transplant supervising center) and intensive care units of donating hospitals. With its success in Saudi Arabia, it is hoped that it will be widely adopted in other regions.

Organ Transplants in Kazakhstan.

The Republic of Kazakhstan is one of the fastest developing countries in the world and has a health care system that is unique in Central Asia. Its organ transplant services are also developing rapidly. We aimed to analyze and briefly report on the current status of organ transplant in the Republic of Kazakhstan. We analyzed organ transplant activities in that country for the period 2012 to 2014. All data were collected from the official database of the National Transplant Coordinating Center of the Republic of Kazakhstan. At the end of 2014, the number of transplant centers had increased to 10, three of which could perform multiorgan transplants; during the same period, the number of deceased-donor organ-donating hospitals increased up to 37. By 2013, the transplant activity rate for all centers had reached 9.22 per million population. During the previous 3 years (2012-2014), there was a 3-fold increase in the number of living donors and an 18-fold increase in the number of kidney transplants. Between 2012 and 2014, the number of living-donor liver transplants increased from 17 to 25, and the number of deceased-donor transplants increased from 3 to 7. During the last 3 years (2012-2014), the number of heart transplants increased to 7 cases. During the last 3 years (2012-2014), Kazakhstan achieved a significant improvement in the organization of its transplant services, and a noticeable upward trend in the system continues.

Optimal management of young adult transplant recipients: the role of integrated multidisciplinary care and peer support.

Young adults with chronic diseases do not fit easily into an aging adult patient population and are frequently isolated from peers. The result is a high rate of non-adherence with medical care and therapy, resulting in poor outcomes. This is an important clinical problem shared equally by young adults transitioning from pediatric care and those presenting directly to adult care. An integrated multidisciplinary pediatric-adult service can improve the transition process and preparation of the teenager for adult health care. A seamless transition into a dedicated young adult service results in reduced premature failure rates of kidney transplants and improved clinic and medication adherence.

Attenuation of rat chronic small bowel allograft rejection by n-3 polyunsaturated fatty acids is associated with reduced expression of graft IL-15.

Interleukin-15 was found to play key roles in various immunological processes including chronic rejection after renal and cardiac transplantation. n-3 polyunsaturated fatty acids (n-3 PUFA) have shown beneficial effects to chronic allograft rejection. The objective of this study is to search the possible mechanism of this inhibitory effect in chronic small bowel allograft rejection. Animals were divided into three groups: isograft (CsA + corn oil-supplemented diet); allograft (CsA + corn oil-supplemented diet); and allograft (CsA + fish oil-supplemented diet). Donor intestines from F344 rats were transplanted orthotopically into Lewis rat recipients. CsA was administered at 5 mg/kg/day for 2 wk post-operatively. Post-transplant weight was recorded. Histopathological changes and graft IL-15 expression were measured on POD 90. Chronic small bowel allograft rejection developed on POD 90. n-3 PUFA significantly decreased the score of chronic rejection and increased the post-operative weight gain rate. This attenuation is associated with reduced graft IL-15 expression. n-3 PUFA contributed to improved pathological and clinical outcome during chronic small bowel allograft rejection, and this improvement was associated with reduced graft IL-15 expression.

Immunossupressant and organ transplantation: immunophilins targeting agent and alternative therapies.

Since the first attempt to replace a dysfunctional organ, clinics and scientific had to overcome many setbacks in order to warrant the success and viability of both the organ and the receptor. Despite the improvement of surgical procedures, some grafts fail within the following days or week due to immunologic rejection. Many ongoing researches are still seeking the perfect immunossupresors. Calcineurin targeting agents have been consolidated as a worldwide immnunossupressant therapy, but due to its widely functional role in many cell types, this strategy often represents a highly risk therapy due to side effects observed with these agents. Here we summarized the latest and past knowledge regarding immunossupression therapies, including the promising and widely used Immunophilin-targeting antagonist therapies.

Mycophenolate mofetil: An update.

Mycophenolic acid (MPA) is a potent, selective, noncompetitive and reversible inhibitor of inosine-5'-monophosphate deshydrogenase (IMPDH). By depleting guanosine and deoxyguanosine nucleotides in T and B lymphocytes it inhibits their proliferation and, hence, immunoglobin (Ig) production. MPA also suppresses dendritic cell maturation decreasing its capacity of antigen presentation to T lymphocytes. MPA reduces the recruitment of monocytes into sites of graft rejection and inflammation. Mycophenolate mofetil (MMF) is a prodrug of MPA that was developed to improve the bioavailability of MPA. After oral administration, MMF is completely metabolized to MPA. A major inactive metabolite, mycophenolic acid glucuronide (MPAG), is formed after MPA glucuronidation. MPAG has an important role in the enterohepatic recirculation of MPA. MMF is approved for the prophylaxis of allograft rejection after renal, cardiac or liver transplant. The oral dose ranges from 1.0-1.5 g/day twice daily. Moreover, studies on the use of MMF in lung and simultaneous pancreas/ kidney transplants have shown encouraging results. MMF also demonstrates potential in the treatment of autoimmune diseases such as lupus, myasthenia gravis and glomerular disorders. This review focuses on the molecular mechanism of action and pharmacological characteristics of MPA. Studies in both approved and nonapproved applications are also summarized.

Preservation of organs from brain dead donors with hyperbaric oxygen.

Hyperbaric oxygen therapy is a technology that involves oxygen treatment at supra-atmospheric pressures in high concentrations, generating increased levels of physically dissolved oxygen in blood plasma. This form of transported oxygen, compared with oxygen chemically bound to hemoglobin, is able to enter tissues with minimal or almost no blood flow. Experimental studies have suggested that hyperoxemia provided by hyperbaric oxygen may be beneficial in the treatment of reperfusion injury. Organs procured from brain-dead hyperbaric oxygen-treated donors may have less cellular injury from ischemia, reperfusion, and no-reflow phenomenon, thus yielding organs in an optimized state for transplantation. This current report consists of a gratifying experience about hyperbaric oxygen treatment playing a possible role on preservation of donor organs in vivo. In the siblings reported here, improved organ function prior to transplantation and the successful organ functioning after transplantation suggests the possible beneficial effect of hyperbaric oxygen treatment on the ischemic insult generated from brain death and repetitive cardiac arrests. Hyperbaric oxygen seems to be a promising candidate as a bridge to transplantation, keeping the donated organs viable until the harvesting procedure can take place for potential brain dead donors. This experience may lead to further investigations on hyperbaric oxygen's role in donor organ preservation.

Mycosis fungoides after solid-organ transplantation: report of 2 new cases.

Long-term survival after solid-organ transplantation is increasing because of recent advances, including new immunosuppressive regimens to avoid graft rejection. However, the resultant modification of the immune system is associated with an increased risk of several cancers. The most common are skin cancers, and lymphomas are second in frequency. Nevertheless, posttransplant primary cutaneous lymphomas (PCLs) are rare, and their incidence is not well known currently. From the files of the Nephrology and Cardiology Departments of University Hospital "12 de Octubre" of Madrid, we obtained clinical data from 1612 transplanted patients and only found 2 cases of posttransplant PCLs, both were T-cell PCL. We reviewed the clinical, histopathological, and immunohistochemical characteristics; both cases were T-cell posttransplant PCLs manifested clinically as mycosis fungoides. One was a 57-year-old woman who had received a cadaveric kidney transplant, and the other was a 60-year-old man with a heart transplant. Histology and immunohistochemistry were consistent with the features of mycosis fungoides when lesions were completely developed. Up to 20% of all organ transplant recipients will suffer some form of malignancy. Unlike general population, 70% of PCLs in transplant recipients are B cell in origin and frequently show positivity for Epstein-Barr virus markers; whereas only 30% are cutaneous T-cell lymphomas. Different pathogenic hypothesis including reduced immune surveillance, chronic antigenic stimulation by transplant grafts, and the direct oncogenic effects of immunosuppressive drugs have been suggested. Although cutaneous B-cell lymphomas are more common, dermatopathologists should be aware that cutaneous T-cell lymphomas may also appear.

Photopheresis in solid organ transplant rejection.

Photopheresis has become a key component in the therapeutic armamentarium of cutaneous T-cell lymphoma, graft-versus-host disease following stem cell transplant, and allograft rejection of solid organs such as heart. Although it is considered a new treatment modality in its present form, the field of phototherapy dates back thousands of years. In this review, the reader will learn more about the history of photopheresis and how it became a therapeutic alternative for patients with solid organ transplants. An extensive literature search will highlight the evidence-based benefits of photopheresis (or lack thereof). A discussion of the mechanism of action of photopheresis and the technical aspects of the procedure will also be covered. Since photopheresis may be the best tolerated form of immunomodulation, current promising, albeit preliminary data on its efficacy warrant further investigation and understanding.

Preservation of rat aortic tissue transplant with green tea polyphenols.

Green tea polyphenols have recently attracted medical attention as bioactive agents with anticancer, antimicrobial, and antiviral effects. We discovered their new usage as preservative agents for tissue transplants. We preserved rat aortas in a DMEM solution containing polyphenols extracted from green tea leaves. The preserved aortas retained original structures and mechanical strength, and were devoid of any undesirable cell secretions for over a month under physiological conditions. In addition, aortas from Lewis rats preserved for a month and transplanted to allogenic ACI rats completely avoided rejection by the host, suggesting that the polyphenols have immunosuppressive actions on the aortic tissues. From these results, we conclude that polyphenol treatment of aortic tissue transplant can maintain its viability for extended periods of time either before or after transplantation, and the method can be applicable to other transplantation situations.

Nutritional complications and management of intestinal transplant.

Advances in intestinal transplantation provide a promising alternative to patients with intestinal failure and chronic dependence on total parenteral nutrition. However, many physiologic complications arising from the surgical procedure and high-dose immunosuppression, along with potential for rejection and infection, make successful graft function after transplantation a challenge. Nutrition issues unique to this patient population include recovery of normal intestinal motility and absorptive capacity. Diarrhea and high stomal output, which are common postoperatively, lead to deficits in macronutrients and micronutrients, especially electrolytes. Impaired gastrointestinal function affects ability to wean patients off hyperalimentation and enable them to tolerate nutrients enterally. In pediatric recipients of intestinal transplant, lack of experience with food or prior food aversions can lead to refusal to eat after transplant--additional challenges to achieving oral intake. Early and aggressive nutrition intervention is necessary for resolution of nutritional deficits and health of donor small bowel. This article presents an overview of the surgical procedure of intestinal transplantation and describes the physiologic adaptations that occur after the process. A case study demonstrates the clinical and nutritional hurdles associated with an intestinal transplant in a child and how dietitians can provide nutrition management. The potential role of individual nutrients in recovery of the transplanted bowel is also discussed.

Tissue engineering in cardiovascular surgery: new approach to develop completely human autologous tissue.

OBJECTIVE: In cardiovascular tissue engineering, three-dimensional scaffolds serve as physical supports and templates for cell attachment and tissue development. Currently used scaffolds are still far from ideal, they are potentially immunogenic and they show toxic degradation and inflammatory reactions. The aim of this study is to develop a new method for a three-dimensional completely autologous human tissue without using any scaffold materials. METHODS: Human aortic tissue is harvested from the ascending aorta in the operation room and worked up to pure human myofibroblasts cultures. These human aortic myofibroblasts cultures (1.5x10(6) cells, passage 3) were seeded into 15-cm culture dishes. Cells were cultured with Dulbecco' s modified Eagle's medium supplemented with 1 mM L-ascorbic acid 2-phosphate for 4 weeks to form myofibroblast sheets. The harvested cell sheets were folded to form four-layer sheets. The folded sheets were then framed up and cultured for another 4 weeks. Tissue development was evaluated by biochemical assay and light and electron microscopy. RESULTS: After 4 weeks of culture in ascorbic acid supplemented medium, myofibroblasts formed thin cell sheets in culture dishes. The cell sheets presented in a multi-layered pattern surrounded by extracellular matrices. Cultured for additional 4 weeks on the frames, the folded sheets further developed into more solid and flexible tissues. Light microscopy documented a structure resembling to a native tissue with confluent extracellular matrix. Under transmission electron microscope, viable cells and confluent bundles of striated mature collagen fibers were observed. Hydroxyproline assays showed significant increase of collagen content after culturing on the frames and were 80.5% of that of natural human pericardium. CONCLUSIONS: Improved cell culture technique may render human aortic myofibroblasts to a native tissue-like structure. A three-dimensional completely autologous human tissue may be further developed on the base of this structure with no show toxic degradation or inflammatory reactions.

[Gaseous oxygen for protection and conditioning of organs during ischemia]. / Gasförmiger Sauerstoff zur Protektion und Konditionierung von Organen in Ischämie.

During organ ischemia, oxygen (O2) is the first "substrate", which is depleted. However, during ischemic storage in hypothermia (0-4 degrees C), a sufficient oxygenation is attainable by means of gaseous O2. The results of organ preservation were (mostly) better than those obtained with other methods at the respective times. O2 can be supplied via organ surfaces: Applying high O2-pressures (3040-15,200 hPa), ileum and lungs or hearts had some functions after 48 and 72 h storage, respectively; life-supporting functions regained kidneys and pancreas after 48 and 22 h storage, respectively. At normobaric conditions, intestine supplied with O2 via its lumen had during ischemic storage an aerobic metabolism and a better post-ischemic function. Using the "two-layer-method" (TLM), pancreas was stored for 96 h and after 90 min anaerobic warm ischemia (aWI) for 48 h with life-supporting functions after transplantation (Tx). Ischemic organs can be persufflated normobarically with gaseous O2 via their vessels. Hearts, skeletal muscles and kidneys in normothermia or frogs' spinal cords-remained viable for many hours. In hypothermia, kidneys damaged by 30 or 60 min aWI could be preserved for 48 and 24 h, respectively, with life-supporting functions after Tx. Hearts subjected to several hours of aerobic ischemia performed post-ischemically better. Livers aerobically stored for 48 h, or for 24 or 4 h after 30 or 60 min aWI, respectively, exhibited greatly improved post-ischemic functions. After 60 min aWI and 2 h persufflation for reconditioning, livers could be stored for another 22 h period of anaerobic ischemia. With normobaric O2-persufflation or TLM during ischemia, energy supply in form of ATP and its demand-meeting utilisation during hypothermia are apparently guaranteed, so that even longer periods of ischemia for Tx-related measures can be overcome. Not only the maintenance of cell and organ integrity or of cellular functions, but also the repair of damaged structures and functions have become possible with less expenditures and risks than with perfusion. The composition of the solutions for preservation or reconditioning of the ischemic organs is pivotal.