Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.

Immunosuppressive drugs in organ transplant recipients--rationale for critical selection

Transplantation is the treatment of choice for many different organ failures. Despite growing experience in surgery and immunosuppression protocols, the long-term mortality of the procedure remains much higher than in the general population. Second only to cardiovascular diseases as the cause of death in organ transplant recipients, cancer is now known to be at least partly related to the immunosuppression regimen. Nevertheless, if calcineurin inhibitors have a demonstrated pro-oncogenic effect, other classes, such as mTOR inhibitors, are antiproliferative, and even demonstrated as an efficient therapy in some advanced oncological situations. Therefore, the adaptation of the therapy protocol evolves now towards an individualized medicine based on the risk factors of each transplant recipient in terms of cardiovascular, infectious and oncological diseases. As the first organ involved by tumor is the skin, many different guidelines have been published to try and adapt the therapy to the occurrence of a new lesion. If, for example, limited actinic keratosis or the first episode of a non-melanoma skin cancer usually requires no change of the immunosuppressive therapy, but a local specialized care and frequent clinical controls, more advanced lesions imply the adaptation of the drug regimen. In any case, the collaboration between general practitioners, dermatologists and the transplantation team is mandatory.

Pre- and posttransplant management of solid organ transplant recipients: risk-adjusted follow-up

Solid organ transplant recipients (SOTR) have an increased risk of skin cancer due to their long-term immunosuppressive state. As the number of these patients is increasing, as well as their life expectancy, it is important to discuss the screening and management of skin cancer in this group of patients. The role of the dermatologist, in collaboration with the transplant team, is important both before transplantation, where patients are screened for skin lesions and the individual risk for skin cancer development is assessed, and after transplantation. Posttransplant management consists of regular dermatological consultations (the frequency depends on different factors discussed below), where early skin cancer screening and management, as well as patient education on sun protective behavior is taught and enforced. Indeed, SOTR are very sensitive to sun damage due to their immunosuppressive state, leading to cumulative sun damage which results in field cancerization with numerous lesions such as in situ squamous cell carcinoma, actinic keratosis and Bowen's disease. These lesions should be recognized and treated as early as possible. Therapeutic options discussed will involve topical therapy, surgical management, adjustment of the patient's immunosuppressive therapy (i.e. reduction of immunosuppression and/or switch to mammalian target of rapamycin inhibitors) and chemoprevention with the retinoid acitretin, which reduces the recurrence rate of squamous cell carcinoma. The dermatological follow-up of SOTR should be integrated into the comprehensive posttransplant care.

[How the bovine viral diarrhea virus outwits the immune system]

The interaction of bovine viral diarrhea virus (BVD virus) with its host has several unique features, most notably the capacity to infect its host either transiently or persistently. The transient infection stimulates an antiviral immune reaction similar to that seen in other transient viral infections. In contrast, being associated with immunotolerance specific for the infecting BVD viral strain, the persistent infection differs fundamentally from other persistent infections like those caused by lentiviruses. Whereas the latter are characterized by complex viral evasion of the host's adaptive immune response by mechanisms such as antigenic drift and interference with presentation of T cell epitopes, BVD virus avoids the immune response altogether by inducing both humoral and cellular immune tolerance. This is made possible by invasion of the fetus at an early stage of development. In addition to adaptive immunity, BVD virus also manipulates key elements of the host's innate immune response. The non-cytopathic biotype of BVD virus, which is capable of persistently infecting its host, fails to induce type I interferon. In addition, persistently infected cells are resistant to the induction of apoptosis by double-stranded RNA and do not produce interferon when treated with this pathogen-associated molecular pattern (PAMP) that signals viral infection. Moreover, when treated with interferon, cells persistently infected with non-cytopathic BVD virus do not clear the virus. Surprisingly, however, despite this lack of effect on persistent infection, interferon readily induces an antiviral state in these cells, as shown by the protection against infection by unrelated viruses. Overall, BVD virus manipulates the host's interferon defense in a manner that optimises its chances of maintaining the persistent infection as well as decreasing the risks that heterologous viral infections may carry for the host. Thus, since not all potential host cells are infected in animals persistently infected with BVD virus, heterologous viruses replicating in cells uninfected with BVD virus will still trigger production of interferon. Interferon produced by such cells will curtail the replication of heterologous viruses only, be that in cells already infected with BVD virus, or in cells in which the heterologous virus may replicate alone. From an evolutionary viewpoint, this strategy clearly enhances the chances of transmission of BVD virus to new hosts, as it attenuates the negative effects that a global immunosuppression would have on the survival of persistently infected animals.

Reversible encephalopathy complicating post-streptococcal glomerulonephritis

We describe a 15-year-old boy with acute transient encephalopathy complicating poststreptococcal glomerulonephritis. Based on advanced magnetic resonance imaging, cerebral alterations were related to cerebrovascular autoregulatory dysfunction (ie, a vasogenic edema) and vasculitis was excluded. These insights into the pathophysiology improve patient management and argue against the therapeutic immunosuppression postulated by some authors.

Mechanisms of airway obliteration after lung transplantation

Post-transplant bronchiolitis obliterans, also called bronchiolitis obliterans syndrome, affects up to 50-60% of patients who survive 5 yr after surgery according to its clinical definition, which is based on the degree of obstructive airway disease. Alloimmune-independent and -dependent mechanisms produce injuries and inflammation of epithelial cells and subepithelial structures, leading to aberrant tissue repair. The triggering of innate immunity by various infections or chemical injuries after, for example, gastroesophageal reflux, may lead to the release of danger signals that are able to activate dendritic cells, a crucial link with adaptive immunity. Inflammation can also increase the expression and display of major histocompatibility alloantigens and thus favor the initiation of rejection episodes. These phenomena may be limited in time and location or may be protracted. Reducing the risk of alloimmune-independent factors may be as important as treating acute episodes of lung rejection. Excessive immunosuppression may be deleterious by increasing the risk of infection, thereby triggering innate and adaptive immunity. New potential therapeutic targets are emerging from the research performed on leukotriene receptors, chemokine receptors, and growth factors. Neutralizing these molecules reduces the initial mononuclear and polynuclear infiltrates or the subsequent fibroproliferative process and the neovascular changes, feeding this process.

Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression

Previous studies demonstrated that impaired left ventricular (LV) relaxation in cardiac allografts limits exercise tolerance post-transplant despite preserved systolic ejection fraction (EF). This study tested in human cardiac allografts whether the isovolumic relaxation time (IVRT), which provides the basis for most of diastolic LV filling, relates with gene expression of regulatory proteins of calcium homeostasis or cardiac matrix proteins. Gene expression was studied in 31 heart transplant recipients (25 male, 6 female) 13-83 months post-transplant with LVEF >50%, LV end-diastolic pressure <20 mmHg, normal LV mass index and without allograft rejection or significant cardiac pathology. IVRT related with the other diastolic parameters e-wave velocity (r = -0.46; p = 0.01), e/a-wave ratio (r = -0.5; p < 0.01) but not with heart frequency (r = -0.16; p = 0.4). No relation of IVRT was observed for immunosuppression, mean rejection grade or other medication. IVRT was not related with gene expression of desmin, collagen I, phospholamban, the Na+-Ca2+ exchanger, the ryanodine receptor or interstitial fibrosis but correlated inversely with SERCA2a (r = -0.48; p = 0.02). Prolonged IVRT is associated with decreased SERCA2a expression in cardiac allografts without significant other pathology. Similar observations in non-transplanted patients with diastolic failure suggest that decreased SERCA2a expression is an important common pathomechanism.

Molecular survival strategies of Echinococcus multilocularis in the murine host

Larval infection with Echinococcus multilocularis starts with the intrahepatic postoncospheral development of a metacestode that-at its mature stage-consists of an inner germinal and an outer laminated layer (GL ; LL). In certain cases, an appropriate host immune response may inhibit parasite proliferation. Several lines of evidence obtained in vivo and in vitro indicate the important bio-protective role of the LL. For instance, the LL has been proposed to protect the GL from nitric oxide produced by periparasitic macrophages and dendritic cells, and also to prevent immune recognition by surrounding T cells. On the other hand, the high periparasitic NO production by peritoneal exsudate cells contributes to periparasitic immunosuppression, explaining why iNOS deficienct mice exhibit a significantly lower susceptibility towards experimental infection. The intense periparasitic granulomatous infiltration indicates a strong host-parasite interaction, and the involvement of cellular immunity in control of the metacestode growth kinetics is strongly suggested by experiments carried out in T cell deficient mouse strains. Carbohydrate components of the LL, such as Em2(G11) and Em492, as well as other parasite metabolites yield immunomodulatory effects that allow the parasite to survive in the host. I.e., the IgG response to the Em2(G11)-antigen takes place independently of alpha-beta+CD4+T cells, and in the absence of interactions between CD40 and CD40 ligand. Such parasite molecules also interfere with antigen presentation and cell activation, leading to a mixed Th1/Th2-type response at the later stage of infection. Furthermore, Em492 and other (not yet published) purified parasite metabolites suppress ConA and antigen-stimulated splenocyte proliferation. Infected mouse macrophages (AE-MØ) as antigen presenting cells (APC) exhibited a reduced ability to present a conventional antigen (chicken ovalbumin, C-Ova) to specific responder lymph node T cells when compared to normal MØ. As AE-MØ fully maintain their capacity to appropriately process antigens, a failure in T cell receptor occupancy by antigen-Ia complex or/and altered co-stimulatory signals can be excluded. Studying the status of accessory molecules implicated in T cell stimulation by MØ, it could be shown that B7-1 (CD80) and B7-2 (CD86) remained unchanged, whereas CD40 was down-regulated and CD54 (=ICAM-1) slightly up-regulated. FACS analysis of peritoneal cells revealed a decrease in the percentage of CD4+ and CD8+T cells in AE-infected mice. Taken together the obstructed presenting-activity of AE-MØ appeared to trigger an unresponsiveness of T cells leading to the suppression of their clonal expansion during the chronic phase of AE infection. Interesting information on the parasite survival strategy and potential can be obtained upon in vitro and in vivo treatment. Hence, we provided very innovative results by showing that nitazoxanide, and now also, respectively, new modified compounds may represent a useful alternative to albendazole. In the context of chemotherapeutical repression of parasite growth, we searched also for parasite molecules, whose expression levels correlate with the viability and growth activity of E. multilocularis metacestode. Expression levels of 14-3-3 and II/3-10, relatively quantified by realtime reverse transcription-PCR using a housekeeping gene beta-actin, were studied in permissive nu/nu and in low-permissive wild type BALB/c mice. At 2 months p.i., the transcription level of 14-3-3 was significantly higher in parasites actively proliferating in nu/nu mice compared to parasites moderately growing in wild type mice. Immunoblotting experiments confirmed at the protein level that 14-3-3 was over-expressed in parasites derived from nu/nu mice at 2 months p.i. In vitro-treatment of E. multilocularis with an anti-echinococcal drug nitazoxanide for a period of 8 days resulted in a significant decrease of both 14-3-3 and II/3-10 transcription levels,

Upregulation of endothelin converting enzyme-1 in host liver during chronic cardiac allograft rejection

Endothelin regulates cytokine expression in vitro and in vivo. This study investigated the effects of chronic allograft rejection on hepatic endothelin-converting enzyme-1 (ECE-1) gene expression and endothelin-1 (ET-1) plasma clearance. Using the Lewis-F344 minor histocompatibility mismatch model of heterotopic cardiac transplantation, hepatic ECE-1 gene expression was measured by real-time polymerase chain reaction and host plasma clearance of ET-1 was measured 8 weeks after transplantation in the absence of immunosuppression. In animals undergoing allograft rejection, hepatic ECE-1 gene expression increased 2-fold (P < 0.05), whereas no effect of rejection on ET-1 clearance from plasma was observed. In summary, upregulation of ECE-1 gene expression occurs in the liver of the host during chronic allograft rejection. Because the liver represents both a key organ for cytokine production and for endothelin metabolism, increased hepatic ECE-1-mediated ET-1 synthesis may contribute to host responses and cytokine production during allograft rejection.

[Acute infectious emergencies in adults in medical practice]

Infectious diseases belong to the most frequent reasons to seek emergency care. Life-threatening infectious emergencies, which require rapid diagnosis and hospitalisation, are, however, rare. Leading signs and symptoms are high fever combined with rapidly deteriorating general conditions, hypotonia, tachycardia, tachypnea, dyspnea, confusion, headache, or petechia or information about asplenia, immunosuppression or recent travel to the tropics. Life threatening situations, such as suspicion of invasive meningococcal infection or bacterial infection in an asplenic patient, septic-toxic shock, and acute bacterial meningitis with delayed hospitalisation require rapid start of empiric antibiotic therapy in the outpatient practice. In addition, acute infectious emergencies comprise situation for which post exposure prophylaxis is indicated.

Pharmacotherapy, vaccines and malaria advice for HIV-infected travellers

Since the introduction of effective antiretroviral therapy (ART), HIV-infected individuals are travelling more frequently and international travel has become much safer. Specific concerns include the safety of ART during travel, drug adherence and interaction considerations, and effects of immunosuppression. This review describes potentially important infections, vaccine effectiveness, safety and special approaches for their use, and HIV-related issues regarding predeparture counselling. With advanced immunosuppression (CD4+ T-cell count < 200/microl or < 14%), the immunogenicity of several vaccines is reduced, complications could occur after live attenuated vaccines and certain infections acquired during travel may be more frequent or severe. Challenges include the best options for malaria chemoprophylaxis, standby treatment and medical follow-up of the increasing number of HIV-infected long-term travellers.

Prevalence of cholecystolithiasis and its management among kidney/pancreas-transplanted type 1 (insulin-dependent) diabetic patients

BACKGROUND: Simultaneous pancreas/kidney transplantation (SPK) should be the procedure of choice for (pre)uremic patients with type 1 diabetes. All standard immunosuppressive protocols for SPK include a calcineurin-inhibitor. Both calcineurin inhibitors, cyclosporine (CyA) and probably tacrolimus (FK506) too, are associated with the occurrence of cholelithiasis due to their metabolic side effects. PATIENTS AND METHODS: We evaluated the prevalence of cholelithiasis in 83 kidney/pancreas transplanted type I-diabetic patients (46 males, 37 females, mean age 42.8 +/- 7.5 years) by conventional B-mode ultrasound 5 years after transplantation. 56 patients received CyA (group 1) and 27 received tacrolimus (group 2) as first-line-immunosuppressive drug. Additional immunosuppression consisted of steroids, azathioprine or mycophenolate mofetil. Additionally, laboratory analyses of cholestasis parameters (gamma-GT and alcalic phosphatasis) were performed. RESULTS: In total, 23 patients (28%) revealed gallstones and 52 patients (62%) revealed a completely normal gallbladder. In eight patients (10%) a cholecystectomy was performed before or during transplantation because of already known gallstones. No concrements in the biliary ducts (choledocholithiasis) could be detected. In group 2 the number of patients with gallstones was slightly lower (22%) compared with group 1 patients (30%), but without statistical significance. - Cholestasis parameters were not increased and HbA1c values were normal in both groups of patients. CONCLUSION: The prevalence of biliary disease in kidney/pancreas transplanted type I-diabetic patients with 28% is increased in comparison to the general population (10-15%). Lithogenicity under tacrolimus seems to be lower as under cyclosporine based immunosuppressive drug treatment. We recommend regular sonographical examinations to detect an acute or chronic cholecystis as early as possible, which may develop occultly in these patients.

Noncompliance in organ transplant recipients: a literature review

The consequences of failing to comply to doctor's instructions can be damaging and devastating for the individual patient and their family. Noncompliance also leads to waste, as it reduces the potential benefits of therapy, and to the extra cost of treating avoidable consequent morbidity. Life-long immunosuppression is a prerequisite for good graft function, and noncompliance is often associated with late acute rejection episodes, graft loss, and death. It might be assumed that transplant patients constitute a highly motivated group, and that compliance would be high. Unfortunately, this is not the case: overall noncompliance rates vary from 20 to 50%. This overview includes literature on heart, liver, and kidney transplants in adult and pediatric transplant patients. Compliance behavior after transplantation, noncompliance and its relationship to organ loss and death, retransplantation outcome after graft loss due to noncompliance, and reasons for postoperative noncompliance will be addressed.

[Noncompliance in organ transplantation: a review]

The effectiveness of medical treatment depends not only on the appropriateness of the treatment modality but also on the patient's compliance with the intended regimen. The consequences of failing to comply can be damaging and devastating for the individual patient and his/her family. Noncompliance also leads to waste in two areas: first, a reduction of the potential benefits of therapy, and second, the additional cost of treating the avoidable consequent morbidity. A dramatic example of the consequences of noncompliance with the treatment regimen concerns patients who have had organ transplants: life-long immunosuppression is a pre-requisite for good graft function, and noncompliance is often associated with the occurrence of late acute rejection episodes, graft loss, and death. Here it might be assumed that these patients constitute a highly motivated group, and that compliance would be high. Unfortunately, this is not the case: overall noncompliance rates vary from 20 to 50%. There is no systematic and comprehensive review of the literature on noncompliance and its consequences in organ transplant patients to date. This overview includes literature on heart, liver and kidney transplants in adult and paediatric transplant patients and addresses the following issues: preoperative behaviour patterns as predictors of postoperative compliance problems, compliance behaviour after transplantation, noncompliance and its relationship to organ loss and death, retransplantation outcome after graft loss due to noncompliance, reasons for postoperative noncompliance, and ways to promote compliance.

Sirolimus and intraoperative hyperthermic peritoneal chemoperfusion with mitomycin-C do not impair healing of bowel anastomoses

Surgeons will increasingly have to address the development of gastrointestinal disease in transplant patients or deal with extended bowel resection and bowel anastomosis in advanced cancer patients. Immunosuppressants as well as intraoperative hyperthermic peritoneal chemoperfusion (IHPC) may alter intestinal anastomotic healing. We evaluated the effects of the immunosuppressant sirolimus and of IHPC on healing and stability of bowel anastomoses in pigs. Twenty-four pigs were divided into four groups (SIR: sirolimus was administered orally; IHPC: animals received IHPC with mitomycin-C; COMP: combination of sirolimus and IHPC was administered; CON: sham-treated control group). Animals underwent hand-sutured small bowel and left colon anastomoses and were killed on postoperative day 4. Anastomoses were evaluated by morphometric analysis and immunohistochemistry (IHC) and by measuring the bursting pressure (BP). In all experimental groups (SIR, IHPC, COMP), anastomotic BPs remained unaltered and were not statistically different compared with control (CON). In addition, ileum villous height and colonic crypt depth analysis revealed no significant difference in mucosal thickness, and IHC showed no difference among groups in proliferation, as assessed by the number of KI-67- and bromodeoxyuridine-labeled cells. Immunosuppression with sirolimus as well as IHPC with mitomycin-C do not alter healing of intestinal anastomosis in pigs.