Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus--results of a multicenter trial

In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

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.

The Effect Of Osteoprotection On Immune Reconstitution Post Bone Marrow Transplant

Specialized microenvironments have been known to strongly influence stem cell fate in hematopoiesis. The interplay between osteolineage cells, specifically the mature osteoblast, and the hematopoietic stem cell (HSC) niche have been of particular note. Recently, preliminary unpublished data obtained in the Scadden laboratory suggests the critical role of the osteoblast in regulating T cells. The goal of this project was to initially determine whether stimulating the osteoblast in the HSC niche leads to increased immune reconstitution after hematopoietic stem cell transplant (HSCT). These results indicated that while bone manipulation pre-transplant may have a positive effect on T and B lymphocyte cell recovery, bone manipulation post-transplant seems to have a suppressing effect. Additionally, stimulation of the osteoblast may have an inhibitory effect on the regeneration of GR1+ myeloid cells. Based on these results, we then sought to determine how osteoprotection pre-HSCT modifies the kinetics of graft-versus-host disease (GVHD) and impacts the regeneration of immune cells. The data from this phase of my experiment suggests a possible immediate benefit in stimulation of the osteoblast in response to GVHD prior to HSCT. The overall results from my thesis project demonstrate a promising relationship between pre-HSCT stimulation of the osteoblast and lymphocyte recovery post-HSCT. ¿

Seasonal variations of ventricular arrhythmia clusters in defibrillator recipients

BACKGROUND: Clustering ventricular arrhythmias are the consequence of acute ventricular electrical instability and represent a challenge in the management of the growing number of patients with an implantable cardioverter-defibrillator (ICD). Triggering factors can rarely be identified. OBJECTIVES: Several studies have revealed seasonal variations in the frequency of cardiovascular events and life-threatening arrhythmias, and we sought to establish whether seasonal factors may exacerbate ventricular electrical instability leading to arrhythmia clusters and electrical storm. METHODS: Two hundred and fourteen consecutive defibrillator recipients were followed-up during 3.3 +/- 2.2 years. Arrhythmia cluster was defined as the occurrence of three or more arrhythmic events triggering appropriate defibrillator therapies within 2 weeks. Time intervals between two clusters were calculated for each month and each season, and were compared using Kruskal-Wallis test and Wilcoxon-Mann-Whitney test with Bonferroni adjustment. RESULTS: During a follow-up of 698 patient years, 98 arrhythmia clusters were observed in 51 patients; clustering ventricular arrhythmias were associated with temporal variables; they occurred more frequently in the winter and spring months than during the summer and fall. Accordingly, the time intervals between two clusters were significantly shorter during winter and spring (median and 95% CI): winter 16 (5-19), spring 11.5 (7-25), summer 34.5 (15-55), fall 50.5 (19-65), P = 0.0041. CONCLUSION: There are important seasonal variations in the incidence of arrhythmia clusters in ICD recipients. Whether these variations are related to environmental factors, change in physical activity, or psychological factors requires further study.

Endovascular stenting of a renal transplant vein

We describe successful endovascular stenting of a high-grade stenosis of a renal transplant vein in a 53-year old patient. Kidney transplantation had been performed due to IgA nephropathy and the patient had become symptomatic two months after uneventful recovery from operation.

Effect of donor-specific transfusions on the outcome of renal allografts in the cyclosporine era

Despite the introduction of new immunosuppressive agents, a steady decline of functioning renal allografts after living donation is observed. Thus nonpharmacological strategies to prevent graft loss have to be reconsidered, including donor-specific transfusions (DST). We introduced a cyclosporine-based DST protocol for renal allograft recipients from living-related/unrelated donation. From 1993 to 2003, 200 ml of whole blood, or the respective mononuclear cells from the potential living donor were administered twice to all of our 61 recipient candidates. The transplanted subjects were compared with three groups of patients without DST from the Collaborative Transplant Study (Heidelberg, Germany) during a 6-year period. Six patients were sensitized without delay for a subsequent cadaveric kidney. DST patients had less often treatment for rejection and graft survival was superior compared with subjects from the other Swiss transplant centers (n = 513) or from Western Europe (n = 7024). To diminish the probability that superior results reflect patient selection rather than effects of DST, a 'matched-pair' analysis controlling for relevant factors of transplant outcome was performed. Again, this analysis indicated that recipients with DST had better outcome. Thus, our observation suggests that DST improve the outcome of living kidney transplants even when modern immunosuppressive drugs are prescribed.

Arterial stiffness assessed by digital volume pulse correlates with comorbidity in patients with ESRD

BACKGROUND: Digital volume pulse (DVP), a noninvasive method for indirect assessment of arterial stiffness, was not tested previously in patients with end-stage renal disease (ESRD). Therefore, we compared the DVP-derived stiffness index (SI(DVP)) with aortic pulse wave velocity (PWV) determined by means of Doppler ultrasonography in 2 groups of patients with ESRD and analyzed the correlation between SI(DVP) and comorbidity. METHODS: Photoplethysmography was performed on the index finger of the dominant hand or the hand from the nonfistula arm in 49 renal transplant (TX) recipients and 48 hemodialysis (HD) patients. Pulse curves were analyzed with computer assistance. Comorbidity was assessed by using an established index. RESULTS: The intrasubject variability of SI(DVP) was 5.7%. SI(DVP) and aortic PWV values correlated significantly (r = 0.66; P = 0.001) in patients with ESRD. SI(DVP) could not be assessed reliably in 25% and 6% of HD patients and TX recipients, respectively. Multivariate regression analyses showed that SI(DVP) increased with age in both HD patients and TX recipients (r = 0.61; P < 0.001) and with systolic blood pressure (r = 0.53; P < 0.025), mean arterial pressure (r = 0.47; P < 0.05), and pulse pressure (r = 0.52; P = 0.02) in TX recipients. Severity of comorbid status was associated highly with individual residuals of age-adjusted SI(DVP) in HD patients and TX recipients (P < 0.001). CONCLUSION: DVP allows the measurement of arterial stiffness in most, but not all, patients with ESRD. SI(DVP) values correlate with comorbidity in HD patients and TX recipients.

Haematopoietic stem cell transplantation in Switzerland. Report from the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) Registry 1997-2003

In 1997, the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) initiated a mandatory national registry for all haematopoietic stem cell transplants (HSCT) in Switzerland. As of 2003, information was collected of 2010 patients with a first HSCT (577 allogeneic (29%) and 1433 autologous (71%) HSCT) and 616 additional re-transplants. This included 1167 male and 843 female patients with a median age of 42.4 years (range 0.2-76.6 years). Main indications were leukaemias (592; 29%) lymphoproliferative disorders (1,061; 53%), solid tumours (295; 15%) and non-malignant disorders (62; 3%). At the time of analysis 1,263 patients were alive (63%), 747 had died (37%). Probability of survival, transplant related mortality or relapse at 5 years was 52%, 21%, 36% for allogeneic and 54%, 5%, 60% for autologous HSCT. Outcome depended on indication, donor type, stem cell source and age of patient. HSCT is an established therapy in Switzerland. These data describe current practice and outcome.

Tissue-transplant fusion and vascularization of myocardial microtissues and macrotissues implanted into chicken embryos and rats

Cell-based therapies and tissue engineering initiatives are gathering clinical momentum for next-generation treatment of tissue deficiencies. By using gravity-enforced self-assembly of monodispersed primary cells, we have produced adult and neonatal rat cardiomyocyte-based myocardial microtissues that could optionally be vascularized following coating with human umbilical vein endothelial cells (HUVECs). Within myocardial microtissues, individual cardiomyocytes showed native-like cell shape and structure, and established electrochemical coupling via intercalated disks. This resulted in the coordinated beating of microtissues, which was recorded by means of a multi-electrode complementary metal-oxide-semiconductor microchip. Myocardial microtissues (microm3 scale), coated with HUVECs and cast in a custom-shaped agarose mold, assembled to coherent macrotissues (mm3 scale), characterized by an extensive capillary network with typical vessel ultrastructures. Following implantation into chicken embryos, myocardial microtissues recruited the embryo's capillaries to functionally vascularize the rat-derived tissue implant. Similarly, transplantation of rat myocardial microtissues into the pericardium of adult rats resulted in time-dependent integration of myocardial microtissues and co-alignment of implanted and host cardiomyocytes within 7 days. Myocardial microtissues and custom-shaped macrotissues produced by cellular self-assembly exemplify the potential of artificial tissue implants for regenerative medicine.

Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group

BACKGROUND AND OBJECTIVES: There are no widely accepted criteria for the definition of hematopoietic stem cell transplant -associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM. DESIGN AND METHODS: The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria. Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts' ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final PROPOSAL. RESULTS: The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count <50 x 109/L or 50% or greater reduction from previous counts); (iii) sudden and persistent increase in lactate dehydrogenase concentration; (iv) decrease in hemoglobin concentration or increased transfusion requirement; and (v) decrease in serum haptoglobin. The sensitivity and specificity of this definition exceed 80%. INTERPRETATION AND CONCLUSIONS: The Working Group recommends that the presented criteria of TAM be adopted in clinical use, especially in scientific trials.

[Endovascular therapy of an abdominal aortic aneurysm in a renal transplant recipient]

INTRODUCTION: The indications for endovascular aortic aneurysm repair (EVAR) are mainly established in hostile abdomen, in patients with significant comorbidities which affect the general operability of the patient and, given the necessary infrastructure, also in ruptured aneurysm. Along to those, we present another possible indication in the presence of a kidney allograft in patients with aortic aneurysm. METHODS: Based on a case report of aorto-biiliac stent-graft repair of an infrarenal aortic aneurysm in a patient with renal allograft, a systematic review of the literature was performed of all similar cases concerning surgical therapy in this constellation. RESULTS: EVAR was performed using an aorto-biiliac system (Zenith) Trifab, COOK) in a 61-year-old male patient 11 years after heterotopic renal allotransplantation in the right iliac fossa. Preoperative renal function was normal. Because the donor renal artery was anastomosed to the recipient's external iliac artery the stent-graft was implanted from the left common femoral artery to minimize temporary allograft ischemia. The intra- and postoperative course was uneventful with a follow-up of presently 12 months. A primary type-II endoleak (retroleak from a lumbar artery) is being treated conservatively so far with embolization being a future option. At present there are 15 cases of EVAR in renal allograft patients that have been reported, all of them being successful. DISCUSSION: All data existing in the literature reported to date as well as our own experience justify the first choice of EVAR in morphologically suitable cases. One major advantage of EVAR in this constellation is the avoidance of aortic cross clamping which poses the graft at risk of ischemia. Long-term results will be most important for definite assessment of EVAR. However, contrast media application during the operation and for CT surveillance should be considered as a major disadvantage.

Glucagon, catecholamine and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts

Successful pancreas transplantation in type I diabetic patients restores normal fasting glucose levels and biphasic insulin responses to glucose. However, virtually no data from pancreas recipients are available relative to other islet hormonal responses or hormonal counterregulation of hypoglycemia. Consequently, glucose, glucagon, catecholamine, and pancreatic polypeptide responses to insulin-induced hypoglycemia and to stimulation with arginine and secretin were examined in 38 diabetic pancreas recipients, 54 type I diabetic nonrecipients, and 26 nondiabetic normal control subjects. Glucose recovery after insulin-induced hypoglycemia in pancreas recipients was significantly improved. Basal glucagon levels were significantly higher in recipients compared with nonrecipients and normal subjects. Glucagon responses to insulin-induced hypoglycemia were significantly greater in the pancreas recipients compared with nonrecipients and similar to that observed in control subjects. Glucagon responses to intravenous arginine were significantly greater in pancreas recipients than that observed in both the nonrecipients and normal subjects. No differences were observed in epinephrine responses during insulin-induced hypoglycemia. No differences in pancreatic polypeptide responses to hypoglycemia were observed when comparing the recipient and nonrecipient groups, both of which were less than that observed in the control subjects. Our data demonstrate significant improvement in glucose recovery after hypoglycemia which was associated with improved glucagon secretion in type I diabetic recipients of pancreas transplantation.