Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer

Thrombotic microangiopathy (TMA) has multiple etiologies. In the four disorders described in this review, the primary organ involved is the kidney. Drug-associated TMA can be an acute, immune-mediated disorder or the result of gradual, dose-dependent toxicity. TMA may occur in patients with advanced HIV infection, possibly mediated by angio-invasive infections. TMA following allogeneic hematopoietic stem cell transplantation may also be caused by drug toxicity; the pathogenesis may involve inhibition of vascular endothelial cell growth factor in renal podocytes. Malignancies of many types with systemic microvascular involvement may cause TMA. Recognition that these syndromes may mimic TTP is important to provide appropriate management and to avoid the inappropriate use of plasma exchange treatment.

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.

Cardiac transplantation with hearts from donors after circulatory declaration of death: haemodynamic and biochemical parameters at procurement predict recovery following cardioplegic storage in a rat model

OBJECTIVES: Donation after circulatory declaration of death (DCDD) could significantly improve the number of cardiac grafts for transplantation. Graft evaluation is particularly important in the setting of DCDD given that conditions of cardio-circulatory arrest and warm ischaemia differ, leading to variable tissue injury. The aim of this study was to identify, at the time of heart procurement, means to predict contractile recovery following cardioplegic storage and reperfusion using an isolated rat heart model. Identification of reliable approaches to evaluate cardiac grafts is key in the development of protocols for heart transplantation with DCDD. METHODS: Hearts isolated from anaesthetized male Wistar rats (n = 34) were exposed to various perfusion protocols. To simulate DCDD conditions, rats were exsanguinated and maintained at 37°C for 15-25 min (warm ischaemia). Isolated hearts were perfused with modified Krebs-Henseleit buffer for 10 min (unloaded), arrested with cardioplegia, stored for 3 h at 4°C and then reperfused for 120 min (unloaded for 60 min, then loaded for 60 min). Left ventricular (LV) function was assessed using an intraventricular micro-tip pressure catheter. Statistical significance was determined using the non-parametric Spearman rho correlation analysis. RESULTS: After 120 min of reperfusion, recovery of LV work measured as developed pressure (DP)-heart rate (HR) product ranged from 0 to 15 ± 6.1 mmHg beats min(-1) 10(-3) following warm ischaemia of 15-25 min. Several haemodynamic parameters measured during early, unloaded perfusion at the time of heart procurement, including HR and the peak systolic pressure-HR product, correlated significantly with contractile recovery after cardioplegic storage and 120 min of reperfusion (P < 0.001). Coronary flow, oxygen consumption and lactate dehydrogenase release also correlated significantly with contractile recovery following cardioplegic storage and 120 min of reperfusion (P < 0.05). CONCLUSIONS: Haemodynamic and biochemical parameters measured at the time of organ procurement could serve as predictive indicators of contractile recovery. We believe that evaluation of graft suitability is feasible prior to transplantation with DCDD, and may, consequently, increase donor heart availability.

Successful kidney transplantation from donor with Marfan's syndrome

Marfan's syndrome is caused by mutations in the extracellular matrix protein fibrillin-1 with aortic aneurysm and dissection being its most life-threatening manifestations. Kidney transplantation from donors with Marfan's syndrome has never been reported in the literature, possibly because of reticences due to the underlying connective tissue disease. Here, we report two patients with end-stage renal disease, transplanted with the kidneys from a donor with Marfan's syndrome who died of aortic dissection and cerebral hemorrhage. After delayed graft function in both recipients, renal function normalized with no renovascular complications and negative proteinuria for 6 years in one patient and 2 years in the other patient, who died from an ischemic cerebrovascular insult. Kidneys from organ donors with Marfan's syndrome might be suitable for transplantation.

In utero haematopoietic stem cell transplantation. Experiences in mice, sheep and humans

Early prenatal diagnosis and in utero therapy of certain fetal diseases have the potential to reduce fetal morbidity and mortality. The intrauterine transplantation of stem cells provides in some instances a therapeutic option before definitive organ failure occurs. Clinical experiences show that certain diseases, such as immune deficiencies or inborn errors of metabolism, can be successfully treated using stem cells derived from bone marrow. However, a remaining problem is the low level of engraftment that can be achieved. Efforts are made in animal models to optimise the graft and study the recipient's microenvironment to increase long-term engraftment levels. Our experiments in mice show similar early homing of allogeneic and xenogeneic stem cells and reasonable early engraftment of allogeneic murine fetal liver cells (17.1% donor cells in peripheral blood 4 weeks after transplantation), whereas xenogeneic HSC are rapidly diminished due to missing self-renewal and low differentiation capacities in the host's microenvironment. Allogeneic murine fetal liver cells have very good long-term engraftment (49.9% donor cells in peripheral blood 16 weeks after transplantation). Compared to the rodents, the sheep model has the advantage of body size and gestation comparable to the human fetus. Here, ultrasound-guided injection techniques significantly decreased fetal loss rates. In contrast to the murine in utero model, the repopulation capacities of allogeneic ovine fetal liver cells are lower (0.112% donor cells in peripheral blood 3 weeks after transplantation). The effect of MHC on engraftment levels seems to be marginal, since no differences could be observed between autologous and allogeneic transplantation (0.117% donor cells vs 0.112% donor cells in peripheral blood 1 to 2 weeks after transplantation). Further research is needed to study optimal timing and graft composition as well as immunological aspects of in utero transplantation.

Bridging hyperacute liver failure by ABO-incompatible auxiliary partial orthotopic liver transplantation

Uncontrollable intracranial pressure elevation in hyperacute liver failure often proves fatal if no suitable liver for transplantation is found in due time. Both ABO-compatible and auxiliary partial orthotopic liver transplantation have been described to control such scenario. However, each method is associated with downsides in terms of immunobiology, organ availability and effects on the overall waiting list.

Preischemic iloprost application for improvement of graft preservation: which route is superior in experimental pig lung transplantation: inhaled or intravenous?

BACKGROUND: Optimal allograft protection is essential in lung transplantation to reduce postoperative organ dysfunction. Although intravenous prostanoids are routinely used to ameliorate reperfusion injury, the latest evidence suggests a similar efficacy of inhaled prostacyclin. Therefore, we compared donor lung-pretreatment using inhaled lioprost (Ventavis) with the commonly used intravenous technique. METHODS: Five pig lungs were each preserved with Perfadex and stored for 27 hours without (group 1) or with (group-2, 100 prior aerosolized of iloprost were (group 3) or iloprost (IV). Following left lung transplantation, hemodynamics, Po(2)/F(i)o(2), compliance, and wet-to-dry ratio were monitored for 6 hours and compared to sham controls using ANOVA analysis with repeated measures. RESULTS: The mortality was 100% in group 3. All other animals survived (P < .001). Dynamic compliance and PVR were superior in the endobronchially pretreated iloprost group as compared with untreated organs (P < .05), whereas oxygenation was comparable overall W/D-ratio revealed significantly lower lung water in group 2 (P = .027) compared with group 3. CONCLUSION: Preischemic alveolar deposition of iloprost is superior to IV pretreatment as reflected by significantly improved allograft function. This strategy offers technique to optimize pulmonary preservation.

Transplantation of yeast-infected cardiac allografts: a report of 2 cases

For the first time in the literature to date, we report 2 cases of transplantation of yeast-infected cardiac allografts. In both cases, endocardial vegetations were observed before graft implantation. Microbiologic samples grew yeasts: Rhodotorula glutinis was found close to the left atrial appendage in the first case and Candida parapsilosis was identified in a vegetation located at the base of the tricuspid valve in the second case. We discuss the possible routes of donor organ infection and management of these 2 unusual cases.

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.

[Lung transplantation in chronic obstructive lung diseases]

Lung transplantation (uni- or bilateral) is an accepted treatment option for patients with end-stage chronic obstructive pulmonary disease. Pulmonary function improves significantly and 5-year-actuarial survival is more than 70% at acceptable early mortality rates. Careful evaluation of risks and benefits in necessary because of the known donor-organ shortage and the risks of life-long immunosuppressive treatment. The bronchiolitis obliterans syndrome is still a nonsolved problem in the long-term course after LTx and it can influence late graft function and patient survival.

Myocardial preservation with the UW solution. First European results in clinical heart transplantation

In recent years, there is a growing body of evidence that the University of Wisconsin (UW) solution offers many advantages in organ preservation with regard to preservation quality and time. We, therefore, conducted the first European prospective, randomized, clinical trial comparing myocardial performance after preservation with UW and St. Thomas Hospital (ST) solution. Preliminary results indicated superior heart function after preservation with UW solution.

Nonviral Gene Delivery of Growth and Differentiation Factor 5 to Human Mesenchymal Stem Cells Injected into a 3D Bovine Intervertebral Disc Organ Culture System

Intervertebral disc (IVD) cell therapy with unconditioned 2D expanded mesenchymal stem cells (MSC) is a promising concept yet challenging to realize. Differentiation of MSCs by nonviral gene delivery of growth and differentiation factor 5 (GDF5) by electroporation mediated gene transfer could be an excellent source for cell transplantation. Human MSCs were harvested from bone marrow aspirate and GDF5 gene transfer was achieved by in vitro electroporation. Transfected cells were cultured as monolayers and as 3D cultures in 1.2% alginate bead culture. MSC expressed GDF5 efficiently for up to 21 days. The combination of GDF5 gene transfer and 3D culture in alginate showed an upregulation of aggrecan and SOX9, two markers for chondrogenesis, and KRT19 as a marker for discogenesis compared to untransfected cells. The cells encapsulated in alginate produced more proteoglycans expressed in GAG/DNA ratio. Furthermore, GDF5 transfected MCS injected into an IVD papain degeneration organ culture model showed a partial recovery of the GAG/DNA ratio after 7 days. In this study we demonstrate the potential of GDF5 transfected MSC as a promising approach for clinical translation for disc regeneration.

Impact of Antiviral Preventive Strategies on the Incidence and Outcomes of Cytomegalovirus Disease in Solid Organ Transplant Recipients

We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant recipients. Risk factors associated with CMV disease and graft failure-free survival were analyzed using Cox regression models. One thousand two hundred thirty-nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (D+/R− vs. R+, hazard ratio [HR] 5.36 [95% CI 3.14–9.14], p < 0.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 [95% CI 0.63–2.17], p = 0.63). CMV disease was not associated with a lower graft failure-free survival (HR 1.27 [95% CI 0.64–2.53], p = 0.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure-free survival after a median of 1.05 years of follow-up (HR 1.63 [95% CI 1.01–2.64], p = 0.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.

Incision length for kidney transplantation does not influence short- or long-term outcome: a prospective randomized controlled trial

BACKGROUND: While previous studies suggest advantages of minimally invasive surgery in living donor nephrectomy, similar data are lacking for kidney transplant recipients. Our aim was to prospectively evaluate short- and long-term outcome for kidney transplant recipients, comparing a short transverse (ST) to a classical hockey-stick (HS) incision. METHODS: Sixty-six patients were randomized into two groups: ST vs. HS from January 2008 to May 2010. ST was defined as incision length ≤9 cm and HS as >14 cm. Perioperative data were collected, with evaluation of intra- and postoperative complications and quality of recovery (QoR) score. RESULTS: There were no significant differences in patient demographics, early or long-term postoperative pain. There were no significant differences in QoR scores between the ST and HS group. Predictive for a worse QoR was persisting incisional pain at the 30-month follow-up. Thirty-days mortality, morbidity, and long-term kidney function did not differ between the two groups (p = 1.00, p = 0.62 and p = 0.66, respectively). CONCLUSIONS: Patient satisfaction as well as graft function and patient mortality was not influenced by incision length. With patient and graft safety being paramount, especially in times of organ shortage, incision length should reflect the requirement for a successful transplantation and not be a measure of feasibility.