Left Renal Vein Division for Juxtarenal Aortic Exposure: Influence on Renal Function and Role of the Communicating Lumbar Vein.

BACKGROUND: In this study, we evaluate the outcome of renal function in patients undergoing juxtarenal abdominal aortic aneurysm repair with or without division of the left renal vein with special focus on the role of the communicating lumbar vein. METHODS: A retrospective analysis of prospectively collected data of 110 patients undergoing elective juxtarenal abdominal aortic aneurysm repair between 2000 and 2018 was performed. The demographic characteristics and comorbidities were reviewed in detail and the renal function was analysed pre- and post-operatively. The cohort of patients was split into group A (left renal vein divided) and B (left renal vein mobilised). Group A was further sub-analysed regarding the presence of a communicating lumbar vein on preoperative imaging data (group A+ = vein present, group A- = no communicating lumbar vein present). RESULTS: The patients were matched well regarding their demographic characteristics and comorbidities. In the analysis of renal function, no statistically significant difference could be detected between group A and B. In the sub-analysis of group A, the group with a communicating lumber vein (group A+) turned out to have a significantly better renal function in the long term (sCrea 0.87 vs. 1.51; p = 0.016). CONCLUSION: Ligation of the left renal vein is a safe procedure in surgery of juxtarenal aortic aneurysms regarding the outcome of the renal function. A communicating lumbar vein between the left renal vein and the left ascending lumbar vein seems to play a key role to provide venous drainage after division of the left renal vein.

Novel prefabricated bovine pericardial grafts as alternate conduit for septic aortoiliac reconstruction.

OBJECTIVE: Infection of prosthetic aortic grafts represents a serious complication with high morbidity and mortality. Replacement with autologous material is recommended; however, in its absence, biological material should be favored. In the present retrospective cohort study, we evaluated the short- and midterm results with the use of commercially available prefabricated bovine pericardium grafts (BPGs) used for the management of aortic graft infection or aortic reconstructive surgery in the presence of systemic infection. METHODS: We performed a retrospective analysis of patients in whom BPGs had been used for aortic reconstruction at two vascular centers. Prefabricated vascular pericardium grafts were preferred over other biological reconstruction techniques for selected cases. Comorbidities, procedure-related details, perioperative morbidity, clinical outcomes, and mortality were analyzed. RESULTS: From 2014 to 2019, 21 patients had received BPGs at two Austrian vascular centers. Their median age was 63 years (interquartile range [IQR], 55-71 years), the patients were predominantly male (76%), and the median body mass index was 25.3 kg/m2 (IQR, 21.7-27.3 kg/m2). The major comorbidities included arterial hypertension, peripheral artery disease, smoking, and chronic pulmonary disease. The indications for surgery were vascular graft or endograft infection in 62% and aortic reconstruction in the presence of systemic infection in 38%. Three patients (14%) had aortoenteric fistulas. Surgery was technically successful in all cases. The median follow-up was 21.6 months (IQR, 6.0-34.6 months). The 30-day mortality was 9.5%. The 1- and 2-year overall survival was 84% and 75%, respectively. Of the 21 patients, 89% had remained free of recurrent infection. One of the two reinfections had resolved after treatment of the underlying focus. At 2 years, the primary and assisted primary patency rates were 86% and 94%, respectively. No limbs were lost during follow-up. CONCLUSIONS: Prefabricated BPGs represent a promising alternative for the management of aortic graft infections and aortoiliac reconstruction in the presence of systemic infection.

Insight into the expression of toll-like receptors 2 and 4 in patients with abdominal aortic aneurysm.

An abdominal aortic aneurysm (AAA) is a relatively common, life-threatening disease prevalent in persons over the age of 65. In recent years, an increasing number of studies have suggested that pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), may serve as important regulators in the development of AAAs. In this study, we evaluated the TLR2 and TLR4 expression in the aortic wall and blood of patients with AAA. The TLR2 and TLR4 mRNA expression were significantly higher in the blood of patients with AAA than in the blood of healthy volunteers (p = 0.009 and p = 0.010, respectively). The expression of TLR2 and TLR4 transcripts was also higher in the blood compared with the aortic wall tissue of AAA patients (p = 0.001 for both). Higher TLR2 protein expression was observed in the aortic wall of AAA patients compared with the blood (p = 0.026). A significantly higher concentration of TNF-α and IL-4 in patients with AAA than in healthy volunteers (p < 0.001 for both) was noticed. This study suggests that TLR2 may play a role in the inflammatory response in the aorta, both locally and systemically, in patients with AAA.

Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients.

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy-mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns.

Standardized intraoperative application of an absorbable polysaccharide hemostatic powder to reduce the incidence of lymphocele after kidney transplantation - a prospective trial.

We assessed whether standardized application of an absorbable polysaccharide hemostatic powder (HaemoCer™) has an effect on lymphocele rate after kidney transplantation. For this nonrandomized prospective trial, we first aimed to know our center-specific lymphocele rate diagnosed by ultrasound imaging. We retrospectively assessed all patient records of the elapsed year resulting in a center-specific rate of 20%, this was consistent with literature. The power analysis showed that 108 patients were required to detect a 50% reduction in lymphocele rate. During the prospective study period, 155 patients undergoing kidney transplantation were recruited to receive HaemoCer™ intraoperatively. In two patients, the product accidentally was not used. Six patients were excluded from analysis because of failure to complete follow-up (one early death and five early graft failures). Of the remaining 147 patients, 15 developed lymphoceles, which represents a rate of 10.2%; (95% CI: 6.3-16.2%). Compared to the expected occurrence, this was significantly lower (P = 0.003). Lymphoceles appeared to be associated with preoperative donor-specific antibody, retransplantation and immunoadsorption in HLA or ABO incompatible donors. At our institution, the frequency of lymphoceles after kidney transplantation appeared to be significantly reduced when HaemoCer™ was applied routinely. The magnitude of the effect warrants randomized evaluation.

Humoral Compensation after Bortezomib Treatment of Allosensitized Recipients.

The efficacy of bortezomib monotherapy in desensitizing kidney transplant candidates with preformed donor-specific antibodies remains unclear. We evaluated the effect of bortezomib on preformed antibodies and upstream components of the B cell response in a primate model sensitized by fully mismatched allogeneic skin transplants to provide mechanistic insights regarding the use of bortezomib as a means of desensitization. Bortezomib treatment given intravenously twice weekly for 1 month (1.3 mg/m2 per dose) clearly reduced the numbers of antibody-producing cells and CD38+CD19+CD20- plasma cells in the bone marrow (P<0.05), but donor-specific alloantibody levels did not decrease. We observed a rapid but transient induction of circulating IgG+ B cells and an increased number of proliferating B cells in the lymph nodes after 1 month of treatment. Notably, bortezomib treatment induced germinal center B cell and follicular helper T cell expansion in the lymph nodes. These data suggest that bortezomib-induced plasma cell depletion triggers humoral compensation.

NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis.

BACKGROUND: Neutrophil gelatinase associated lipocalin (NGAL) is expressed in atherosclerotic lesions and was recently implicated in the pathogenesis of cardiovascular pathologies. Statins are known to exert stabilizing effects on atherosclerotic plaque. The aims of our study were (1) to investigate the association of serum NGAL and metalloproteinase (MMP)-9/NGAL complex with the vulnerability of the atherosclerotic plaque, and (2) to reveal the effects of statin treatment on circulating NGAL and MMP-9/NGAL levels in patients with carotid artery stenosis. METHODS: We examined the levels of NGAL and MMP-9/NGAL in blood samples from 136 patients with carotid artery stenosis by specific enzyme-linked immunosorbent assays. RESULTS: Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of American Heart Association [AHA]), displayed the highest levels of NGAL (both p<0.0001) and MMP-9/NGAL complex (p=0.0004 and p=0.004, respectively). Moreover, patients with symptomatic carotid atherosclerosis had significantly higher NGAL levels compared to asymptomatic patients (p=0.0007). The statin-treated group (n=108) demonstrated lower NGAL (73.9 vs. 128.0 µg/L, p<0.0001) and MMP-9/NGAL (28.9 vs. 40.6 µg/L, p=0.046) as compared to the non-statin group (n=28). Furthermore, in multivariate regression analysis NGAL, but not MMP-9/NGAL levels, were independently associated with symptomatic carotid artery stenosis. In addition, statin treatment was independently associated with lower NGAL levels. CONCLUSIONS: Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels.

Plasma HMGB-1 after the initial dose of epirubicin/docetaxel in cancer.

BACKGROUND: The response of breast cancer patients to neoadjuvant chemotherapy (NCT) is highly heterogeneous, and reliable predictive instruments remain to be defined. High-mobility group box-1 (HMGB-1) protein is a cell death marker, which is easily detectable in plasma. We hypothesized that the initial dose of NCT with epirubicin/docetaxel induces changes in plasma HMGB-1 which could allow for an early prediction of response to therapy. MATERIALS AND METHODS: First, we analysed whether epirubicin/docetaxel releases HMGB-1 from HCC1143 breast cancer cells in vitro. Thereafter, plasma HMGB-1 levels before and 1-4 days after the first dose of epirubicin/docetaxel-based NCT were determined in 41 breast cancer patients and correlated with pathological response to treatment. RESULTS: Treatment of HCC1143 cells with epirubicin/docetaxel resulted in a significant HMGB-1 release in vitro. In vivo, HMGB-1 levels increased significantly only in responders (pathological complete response or partial remission, n = 22) but not in nonresponders (stable or progressive disease, n = 19). CONCLUSION: Our data suggest that early dynamic changes of plasma HMGB1 could be a promising biomarker to predict the final response to NCT in breast cancer patients.

Structural failure in bridging stentgrafts for branched endovascular aneurysm repair: a case-control study.

OBJECTIVE: To present a case series of spontaneous structural failure of bridging stentgrafts (BSGs) after branched endovascular aortic repair (bEVAR), as well as their failure types and their detection. While bEVAR is a safe and effective procedure, one main limitation is the reintervention rate associated with the BSGs. Structural failure of BSGs, defined as fabric disruption, stent fracture with leak or complete separation is a major cause for reinterventions and difficult to detect in computed tomography angiography (CTA). METHODS: From a multicenter bEVAR complication database, structural BSG failures were identified. Patient and BSG characteristics, detection mode, failure type, treatment and outcome were recorded and compared with bEVAR patients with intact BSGs. RESULTS: Twenty-three BSG failures were detected in 12 patients with only 43% directly identified in CTA, after a mean of 21.4 months after implantation. The BSGs were Advanta (n = 4), E-Ventus (n = 16) and BeGraft (n = 3) in 10 renal, 9 superior mesenteric, and 4 celiac branches. Religning with another BSG was successful in 20/22 cases, one BSG failure necessitated renal branch embolization (organ loss), and one mesenteric bypass surgery. Two reintervention-related mortalities occurred. CONCLUSION: Structural failure of BSGs is a serious limitation for bEVAR, which can result in high reintervention rates and serious complications. BSG failure typically occurs in single-layer types and events are clustered in patients. The necessary reinterventions carry serious morbidity and mortality. Since the use as BSG in bEVAR is off-label with all current BSG manufacturers, caution is advised regarding patient-informed consent.

Steroid pretreatment of organ donors to prevent postischemic renal allograft failure: a randomized, controlled trial.

BACKGROUND: Posttransplantation acute renal failure (ARF) occurs in roughly 25% of recipients of organs from deceased donors. Inflammation in the donor organ is associated with risk for ARF. OBJECTIVE: To determine whether administering corticosteroids to deceased organ donors reduces the incidence and duration of ARF in organ recipients more than placebo. DESIGN: Parallel, blocked randomized trial, performed between February 2006 and November 2008, with computer-generated randomization and centralized allocation. Investigators were masked to group assignment. (Controlled-trials.com registration number: ISRCTN78828338) SETTING: 3 renal transplantation centers in Austria and Hungary. PATIENTS: 306 deceased heart-beating donors and 455 renal transplant recipients. INTERVENTIONS: Organ donors were administered an intravenous infusion of either 1000 mg of methylprednisolone (136 donors) or placebo (0.9% saline) (133 donors) at least 3 hours before organ harvesting. MEASUREMENTS: Incidence of ARF, defined as more than 1 dialysis session in the first week after transplantation, was the primary end point. Secondary and other end points included duration of ARF and trajectories of serum creatinine level. The suppression of immune response and inflammation by the intervention was assessed in the donor organ on a genome-wide basis. RESULTS: 52 of 238 recipients (22%) of kidneys from steroid-treated donors and 54 of 217 recipients (25%) of kidneys from placebo-treated donors had ARF (difference, 3 percentage points [95% CI, -11 to 5 percentage points]). One graft was lost on day 1 in each group, and 1 recipient in the placebo group died of cardiac arrest on day 2. The median duration of ARF was 5 days (interquartile range, 2 days) in the steroid group and 4 days (interquartile range, 2 days) in the placebo group (P = 0.31). The groups had similar trajectories of serum creatinine level in the first week (P = 0.72). Genomic analysis showed suppressed inflammation and immune response in kidney biopsies from deceased donors who received corticosteroids. LIMITATION: Donors and recipients were mainly white, and all were from 3 transplantation centers in central Europe, which may limit generalizability. CONCLUSION: Systemic suppression of inflammation in deceased donors by corticosteroids did not reduce the incidence or duration of posttransplantation ARF in allograft recipients. PRIMARY FUNDING SOURCE: Austrian Science Fund and Austrian Academy of Science.

Identification of Non-HLA antigens targeted by alloreactive antibodies in patients undergoing chronic hemodialysis.

The only treatment of end-stage renal disease patients undergoing chronic dialysis is kidney transplantation. However, about half of graft recipients encounter organ loss within ten years after renal transplantation. There is emerging evidence that the presence of alloreactive antibodies against non-HLA antigens in the serum of the recipient prior transplantation is associated with higher incidence of chronic rejection. However, the molecular identity of these antigens is largely unknown. To determine the most common non-HLA antigens, we tested lymphocytic extracts from 20 healthy volunteers with sera of 28 patients on the transplantation waiting list by Western blotting. There was a group of five proteins that was recognized by most sera. Using patient's own lymphocytes revealed that autoimmunity plays a minor role in this recognition. Two-dimensional Western blotting experiments followed by mass spectrometry identified the antigens as tubulin beta chain, vimentin, lamin-B1, and Rho GDP-dissociation inhibitor 2. A detailed analysis of vimentin expression revealed that the antigenic 60 kDa isoform is underrepresented in patient's lymphocytes in comparison to those of healthy volunteers. The study revealed that preformed alloreactive antibodies are directed against a small number of specific protein isoforms. Our findings could provide a basis for future improvement of donor-recipient matching.

The value of protecting the longitudinal staple line with invaginating sutures during esophageal reconstruction by gastric tube pull-up.

BACKGROUND: Radical surgery with lymphadenectomy offers the best chance of curing esophageal cancer, but it carries considerable risks. Generally, the resected esophagus is replaced with a gastric tube. Rupture of the gastric tube staple line is a rare but serious surgical complication. One unresolved issue is whether oversewing of the longitudinal gastric staple line is necessary to avoid staple line rupture or insufficiency. PATIENTS AND METHODS: Between 2000 and February 2008, 199 patients underwent esophageal resection for cancer or perforation at the Vienna General Hospital, Medical University of Vienna. Data were collected prospectively. Of these patients, 151 (75.9%) underwent reconstruction by pulling up a gastric tube. These comprised the study population. In 83 patients (55.0%) the longitudinal gastric staple line was not oversewn (group A). In 68 patients (45.0%) the staple line was reinforced by invaginating sutures (group B). RESULTS: The mean age of the patients was 62.0 +/- 10.6 years (median: 63.1 years). Males comprised 75.5% of the population. Adenocarcinoma was diagnosed in 77 patients (51.0%), 63 patients (41.7%) suffered from a squamous cell carcinoma, 10 patients (6.6%) had esophageal perforation, and in 1 patient (0.7%) a gastrointestinal stromal tumor was diagnosed. In group A, a leak within the staple line was observed in 4 of 83 patients (4.9%). No leak was found in group B (p = 0.09). Major surgical complications included anastomotic leakage (21 patients; 13.9%), gastric tip necrosis (3 patients; 2%), postoperative ileus (3 patients; 2.0%) and chylothorax (7 patients; 4.6%). Two major intraoperative complications (1.3%) were splenic injury and aortic bleeding. CONCLUSION: A remarkable but not statistically significant difference was found regarding staple line rupture between study groups. However, all leaks were seen in patients without a staple line suture.

Crosstalk Between T and B Cells in the Germinal Center After Transplantation.

Crosstalk between B and T cells in transplantation is increasingly recognized as being important in the alloimmune response. T cell activation of B cells occurs by a 3-stage pathway, culminating with costimulation signals. We review the distinct T cell subtypes required for B-cell activation and discuss the formation of the germinal center (GC) after transplantation, with particular reference to the repopulation of the GC after depletional induction, and the subsequent effect of immunosuppressive manipulation of T cell-B cell interactions. In addition, ectopic GCs are seen in transplantation, but their role is not fully understood. Therapeutic options to target T cell-B cell interactions are of considerable interest, both as immunosuppressive tools, and to aid in the further understanding of these important alloimmune mechanisms.

Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates.

The detrimental effects of donor-directed antibodies in sensitized transplant patients remain a difficult immunologic barrier to successful organ transplantation. Antibody removal is often followed by rebound. Proteasome inhibitors (PIs) deplete antibody-producing plasma cells (PCs) but have shown marginal benefit for desensitization. In an allosensitized nonhuman primate (NHP) model, we observed increased germinal center (GC) formation after PI monotherapy, suggesting a compensatory PC repopulation mediated via GC activation. Here we show that costimulation blockade (CoB) targets GC follicular helper T (Tfh) cells in allosensitized NHPs. Combined PI and CoB significantly reduces bone marrow PCs (CD19+CD20-CD38+), Tfh cells (CD4+ICOS+PD-1hi), and GC B cells (BCL-6+CD20+); controls the homeostatic GC response to PC depletion; and sustains alloantibody decline. Importantly, dual PC and CoB therapy prolongs rejection-free graft survival in major histocompatibility complex incompatible kidney transplantation without alloantibody rebound. Our study illustrates a translatable desensitization method and provides mechanistic insight into maintenance of alloantibody sensitization.

Lymphocyte activation induces cell surface expression of an immunogenic vimentin isoform.

High titers of anti-vimentin antibodies after transplantation are known to be associated with poor long-term graft survival. Vimentin is an intracellular protein which is present in different isoforms in the cell. In a previous study with sera from hemodialysis patients on the kidney transplantation waiting list we could show that only a 49 kDa and a 60 kDa isoform are recognized by patients' anti-vimentin antibodies while the other isoforms remain undetected. However, it is still unclear whether antibodies against this intracellular protein can bind to intact cells. Here we show that vimentin can be present on the cell surface under certain conditions. Lymphocytes from healthy volunteers were used as a model for allogeneic cells. We could show by immunofluorescence microscopy, flow cytometry and Western blot experiments that concanavalin A (Con A) activated lymphocytes express a 49 kDa vimentin isoform on their cell surface while the 60 kDa isoform remains inaccessible from the outside. This expression is associated with an increased binding of sera from hemodialysis patients which were positive for anti-vimentin antibodies. These results suggest that cell activation enhances binding of anti-vimentin antibodies to intact cells which might contribute to chronic allograft nephropathy.

Peer review versus editorial review and their role in innovative science.

Peer review is a widely accepted instrument for raising the quality of science. Peer review limits the enormous unstructured influx of information and the sheer amount of dubious data, which in its absence would plunge science into chaos. In particular, peer review offers the benefit of eliminating papers that suffer from poor craftsmanship or methodological shortcomings, especially in the experimental sciences. However, we believe that peer review is not always appropriate for the evaluation of controversial hypothetical science. We argue that the process of peer review can be prone to bias towards ideas that affirm the prior convictions of reviewers and against innovation and radical new ideas. Innovative hypotheses are thus highly vulnerable to being "filtered out" or made to accord with conventional wisdom by the peer review process. Consequently, having introduced peer review, the Elsevier journal Medical Hypotheses may be unable to continue its tradition as a radical journal allowing discussion of improbable or unconventional ideas. Hence we conclude by asking the publisher to consider re-introducing the system of editorial review to Medical Hypotheses.

Molecular adsorbent recirculating system in patients with early allograft dysfunction after liver transplantation: a pilot study.

Early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT) causes marked morbidity and mortality. We conducted a prospective pilot study to assess the safety and efficacy of molecular adsorbent recirculating system (MARS) in treatment of EAD after OLT. Twelve consecutive adult liver allograft recipients with a median age of 48 years, 9 of whom were male, were prospectively included and supported with MARS. EAD was defined as the presence of at least 2 of the following: serum bilirubin >10 mg/dL, prothrombin time <40%, aspartate aminotransferase or alanine transferase >1,000 U/L, and plasma disappearance rate of indocyanine green (PDR(ICG)) <10% per minute within 72 hours after reperfusion. One-year patient and graft survival was 66%. There was a significant decrease in serum bilirubin (P = 0.002), serum creatinine (P = 0.006), and aspartate aminotransferase (P = 0.005) and a significant increase in PDR(ICG) (P = 0.007) after MARS treatment. Prothrombin time, albumin level, and platelet count remained stable. Sustained improvement of renal and neurological function and of mean arterial pressure were observed. No MARS-related adverse effects occurred. MARS treatment provides a safe approach to the treatment of EAD after OLT. On the basis of this pilot study, a multicenter randomized clinical trial that uses MARS treatment in EAD after OLT has been initiated.