Acute antibody-mediated rejection after intestinal transplantation

AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection(ABMR) after intestinal transplantation(ITx).METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody(DSA), acute tissue damage, C4 d deposition, and allograft dysfunction.RESULTS Acute ABMR was identified in 18(10.3%) out of 175 intestinal allografts with an average occurrence of 10 d(range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class Ⅰand/or Ⅱ antigens with a detectable DSA. A positive cross-match was seen in 14(77.8%) cases and twelve of 18 patients(66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4 d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibodyas a significant independent risk factor. Despite initial improvement after therapy, eleven recipients(61.1%) lost transplant secondary to rejection. Of those, 9(50%) underwent graft removal and 4(22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo(range, 13.3-76.4), 8(44.4%) recipients died.CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes.

Treatment with plasmapheresis, immunoglobulins and rituximab for chronic-active antibody-mediated rejection in kidney transplantation: Clinical, immunological and pathological results

AIM To evaluate the role of a therapeutic regimen with plasma exchange, intravenous immunoglobulins and rituximab in chronic-active antibody-mediated rejection(c AMR) settings.METHODS We compared 21 kidney transplant recipients(KTRs) with a diagnosis of c AMR in a retrospective casecontrol analysis: nine KTRs treated with plasmapheresis, intravenous immunoglobulins and rituximab(PE-IVIGRTX group) vs 12 patients(control group) not treated with antibody-targeted therapies. We examined kidney survival and functional outcomes 24 mo after diagnosis. Histological features and donor-specific antibody(DSA) characteristics(MFI and C1 q-fixing ability) were also investigated.RESULTS No difference in graft survival between the two groups was noted: three out of nine patients in the PE-IVIG-RTX group(33.3%) and 4/12 in the control group(33.3%) experienced loss of allograft function at a median time after diagnosis of 14 mo(min 12-max 18) and 15 mo(min 7-max 22), respectively. Kidney functional tests and proteinuria 24 mo after cA MR diagnosis were also similar in both groups. Only microvascular inflammation(glomerulitis + peritubular capillaritis score) was significantly reduced after PE-IVIG-RTX in seven out of eight patients(87.5%) in the PE-IVIG-RTX group(median score 3 in pre-treatment biopsy vs 1.5 in post-treatment biopsy; P = 0.047), without any impact on kidney survival and/or DSA characteristics. No functional or histological parameter at diagnosis was predictive of clinical outcome.CONCLUSION Our data showed no difference in the two year posttreatment outcome of kidney grafts treated with PE-IVIGRTX for c AMR diagnosis, however there were notable improvements in microvascular inflammation in posttherapy protocol biopsies. Further studies, especially involving innovative therapeutic approaches, are required to improve the management and long-term results of this severe condition.

Updates on antibody-mediated rejection in intestinal transplantation

Antibody-mediated rejection(ABMR) has increasingly emerged as an important cause of allograft loss after intestinal transplantation(ITx). Compelling evidence indicates that donor-specific antibodies can mediate and promote acute and chronic rejection after ITx. However, diagnostic criteria for ABMR after ITx have not been established yet and the mechanisms of antibodymediated graft injury are not well-known. Effective approaches to prevent and treat ABMR are required to improve long-term outcomes of intestine recipients. Clearly, ABMR after ITx has become an important area for research and clinical investigation.

Metropolis-Hastings Algorithm with Delayed Acceptance and Rejection

Metropolis-Hastings algorithms are slowed down by the computation of complex target distributions. To solve this problem, one can use the delayed acceptance Metropolis-Hastings algorithm (MHDA) of Christen and Fox (2005). However, the acceptance rate of a proposed value will always be less than in the standard Metropolis-Hastings. We can fix this problem by using the Metropolis-Hastings algorithm with delayed rejection (MHDR) proposed by Tierney and Mira (1999). In this paper, we combine the ideas of MHDA and MHDR to propose a new MH algorithm, named the Metropolis-Hastings algorithm with delayed acceptance and rejection (MHDAR). The new algorithm reduces the computational cost by division of the prior or likelihood functions and increase the acceptance probability by delay rejection of the second stage. We illustrate those accelerating features by a realistic example.

Chronic rejection after liver transplantation:Opening the Pandora’s box

Chronic rejection(CR)of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation.Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy,CR still represents an important cause of graft injury,which might be irreversible,leading to graft loss requiring re-transplantation.To date,we still do not fully appreciate the mechanisms underlying this process.In addition to T cell-mediated CR,which was initially the only recognized type of CR,recently a new form of liver allograft CR,antibody-mediated CR,has been identified.This has indeed opened an era of thriving research and renewed interest in the field.Liver biopsy is needed for a definitive diagnosis of CR,but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation.Moreover,the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury,which should not be disregarded.Therapies for CR may only be effective in the“early”phases,and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage.Herein,we provide an overview of the current knowledge and research on CR,focusing on early detection,identification of non-invasive biomarkers,immunosuppressive management,re-transplantation and future perspectives of CR.

Design of a robust guidance law via active disturbance rejection control

Focusing on the three-dimensional guidance problem in case of target maneuvers and response delay of the autopilot, the missile guidance law utilizing active disturbance rejection control （ADRC） is proposed. Based on the nonlinear three-dimensional missile target engagement kinematics, the guidance model is es- tablished, The target acceleration is treated as a disturbance and the dynamics of the autopilot is considered by using a first-order model. A nonlinear continuous robust guidance law is designed by using a cascaded structure ADRC controller. In this method the disturbance is estimated by using the extended state observer （ESO） and compensated during each sampling period. Simulation results show that the proposed cascaded loop structure is a viable solution to the guidance law design and has strong robustness with respect to target maneuvers and response delay of the autopilot.

Risk factors and outcomes of delayed graft function in renal transplant recipients receiving a steroid sparing immunosuppression protocol

AIM To analyse the risk factors and outcomes of delayed graft function(DGF) in patients receiving a steroid sparing protocol. METHODS Four hundred and twenty-seven recipients of deceased donor kidney transplants were studied of which 135(31.6%) experienced DGF. All patients received monoclonal antibody induction with a tacrolimus based, steroid sparing immunosuppression protocol.RESULTS Five year patient survival was 87.2% and 94.9% in the DGF and primary graft function(PGF) group respectively, P = 0.047. Allograft survival was 77.9% and 90.2% in the DGF and PGF group respectively, P < 0.001. Overall rejection free survival was no different between the DGF and PGF groups with a 1 and 5 year rejection free survival in the DGF group of 77.7% and 67.8% compared with 81.3% and 75.3% in the PGF group, P = 0.19. Patients with DGF who received IL2 receptor antibody induction were at significantly higher risk of rejection in the early post-transplant period than the group with DGF who received alemtuzumab induction. On multivariate analysis, risk factors for DGF were male recipients, recipients of black ethnicity, circulatory death donation, preformed DSA, increasing cold ischaemic time, older donor age and dialysis vintage.CONCLUSION Alemtuzumab induction may be of benefit in preventing early rejection episodes associated with DGF. Prospective trials are required to determine optimal immunotherapy protocols for patients at high risk of DGF.

Blessing and a curse of outpatient management of delayed graft function

Delayed graft function (DGF) is a common complication occurring most often after deceased donor kidney transplant with several donor characteristics as well as immunologic factors that lead to its development post-transplant.These patients require dialysis and close kidney function monitoring until sufficient allograft function is achieved.This has resulted in limited options for DGF management,either prolonged hospitalization until graft function improves to the point where dialysis is no longer needed or discharge back to their home dialysis unit with periodic follow up in the transplant clinic.DGF is associated with a higher risk for acute rejection,premature graft failure,and 30-d readmission;therefore,these patients need close monitoring,immunosuppression management,and prompt allograft biopsy if prolonged DGF is observed.This may not occur if these patients are discharged back to their home dialysis unit.To address this issue,the University of Wisconsin-Madison created a clinic in 2011 specialized in outpatient DGF management.This clinic was able to successfully reduce hospital length of stay without an increase in 30-d readmission,graft loss,and patient death.

Human leukocyte antigen and donor-specific antibodies in liver transplantation

In this article,we comment on an article published in a recent issue of the World Journal of Gastroenterology.We specifically focus on the roles of human leukocyte antigen(HLA)and donor-specific antibodies(DSAs)in pediatric liver transpl-antation(LT),as well as the relationship between immune rejection after LT and DSA.Currently,LT remains the standard of care for pediatric patients with end-stage liver disease or severe acute liver failure.However,acute and chronic re-jection continues to be a significant cause of graft dysfunction and loss.HLA mismatch significantly reduces graft survival and increases the risk of acute rejection.Among them,D→R one-way mismatch at three loci was significantly related to graft-versus-host disease incidence after LT.The adverse impact of HLA-DSAs on LT recipients is already established.Therefore,the evaluation of HLA and DSA is crucial in pediatric LT.

Robust PID controller design for time delay processes with peak of maximum sensitivity criteria

The motivation of this work is to obtain single PI/PID tuning formula for different types of processes with enhanced disturbance rejection performance. The proposed tuning formula consistently gives better performance in comparison to several well-known methods at the same degree of robustness for stable, integrating and unstable processes. For the selection of the closed-loop time constant(τc), a guideline is provided over a broad range of time-delay/time-constant ratios on the basis of the peak of maximum sensitivity(Ms). An analysis has been performed for the uncertainty margin with the different process parameters for the robust controller design. It gives the guideline of the Ms-value settings for the PI controller designs based on the process parameters uncertainty. Furthermore, a relationship has been developed between Ms-value and uncertainty margin with the different process parameters(k, τ and θ). Simulation study has been conducted for the broad class of processes and the controllers are tuned to have the same degree of robustness by measuring the maximum sensitivity, Ms, in order to obtain a reasonable comparison.

LESO-based Position Synchronization Control for Networked Multi-Axis Servo Systems With Time-Varying Delay

The position synchronization control(PSC) problem is studied for networked multi-axis servo systems(NMASSs) with time-varying delay that is smaller than one sampling period. To improve the control performance of the system, time-varying delays, modeling uncertainties, and external disturbances are first modeled as a lumped disturbance. Then, a linear extended state observer(LESO) is devised to estimate the system state and the lumped disturbance, and a linear feedback controller with disturbance compensation is designed to perform individual-axis tracking control. After that, a cross-coupled control approach is used to further improve synchronization performance. The bounded-input-bounded-output(BIBO) stability of the closedloop control system is analyzed. Finally, both simulation and experiment are carried out to demonstrate the effectiveness of the proposed method.

Dynamic disturbance rejection controllers for neutral time delay systems with application to a central heating system

In the present paper the problem of disturbance rejection of single input-single output neutral time delay systems with multiple measurable disturbances is solved via dynamic controllers. In particular, the general form of the controller matrices is presented, while the necessary and sufficient conditions for the controller to be realizable are offered. The proposed technique is applied to a test case neutral time delay central heating system. In particular, the nonlinear model of the plant and its linearized approximation are presented. Based on the linearized model, a two-stage controller is designed in order to regulate the room temperature and the boiler effluent temperature. The performance of the closed loop system is investigated through computational experiments.

Liver transplantation: Current status and challenges

Great progress has been made in the field of liver transplantation over the past two decades. This progress, however, also brings up the next set of challenges: First, organ shortage remains a major limitation, and accounts for a large proportion of wait list mortality. While living donation has successfully increased the total number of liver transplants done in Asian countries, the total number of such transplants has been stagnant in the western hemisphere. As such, there has been a significant effort over the past decade to increase the existing deceased donor pool. This effort has resulted in a greater use of liver allografts following donation after cardiac death(DCD) along with marginal and extended criteria donors. Improved understanding of the pathophysiology of liver allografts procured after circulatory arrest has not only resulted in better selection and management of DCD donors, but has also helped in the development of mechanical perfusion strategies. Early outcomes demonstrating the clinical applicability of both hypothermic and normothermic perfusion and its potential to impact patient survival and allograft function have generated much interest. Second, long-term outcomes of liver transplant recipients have not improved significantly, as recipients continue to succumb to complications of long-term immunosuppression, such as infection, malignancy and renal failure. Furthermore, recent evidence suggests that chronic immune-mediated injury to the liver may also impact graft function.

Egg recognition and nestling discrimination in the Crested Myna(Acridotheres cristatellus):Size matters

Most studies exploring abilities of hosts to detect brood parasitism are based on detecting colour and/or pattern differences among parasitic and host eggs or nestlings,while only few were focused on size differences.True recognition and recognition by discordancy are used to explain cognitive mechanisms of host egg recognition;however,only a few studies have found that hosts use recognition by discordancy.This study investigated:1)whether egg and nestling recognitions in the Crested Myna(Acridotheres cristatellus) are based on size cues;2)whether the egg cognitive mechanism is recognition by discordancy based on size cues;and 3) whether the longer the experiment time,the higher the egg recognition rate.Our results showed that the Crested Myna uses egg or nestling size as a recognition cue while the egg and nestling colour and patterning are not associated with egg or nestling rejection,thus the cognitive mechanism of egg recognition in the Crested Myna is recognition by discordancy based on egg size cues.Furthermore,there is a rejection delay in time of egg rejection behaviour of the Crested Myna.Therefore,we suggest that the periodicity of egg rejection experiments could be appropriately extended,especially for species with relatively low egg recognition ability.

Zoeppritz-based AVO inversion using an improved Markov chain Monte Carlo method

The conventional Markov chain Monte Carlo （MCMC） method is limited to the selected shape and size of proposal distribution and is not easy to start when the initial proposal distribution is far away from the target distribution. To overcome these drawbacks of the conventional MCMC method, two useful improvements in MCMC method, adaptive Metropolis （AM） algorithm and delayed rejection （DR） algorithm, are attempted to be combined. The AM algorithm aims at adapting the proposal distribution by using the generated estimators, and the DR algorithm aims at enhancing the efficiency of the improved MCMC method. Based on the improved MCMC method, a Bayesian amplitude versus offset （AVO） inversion method on the basis of the exact Zoeppritz equation has been developed, with which the P- and S-wave velocities and the density can be obtained directly, and the uncertainty of AVO inversion results has been estimated as well. The study based on the logging data and the seismic data demonstrates the feasibility and robustness of the method and shows that all three parameters are well retrieved. So the exact Zoeppritz-based nonlinear inversion method by using the improved MCMC is not only suitable for reservoirs with strong-contrast interfaces and longoffset ranges but also it is more stable, accurate and antinoise.

Impact of donor-specific antibodies on the outcomes of kidney graft:Pathophysiology, clinical, therapy

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donorspecific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens(HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the posttransplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage.These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase Ⅰ-Ⅱ of clinical trials. Thus the pipeline for the near future appears almost empty.

Clinical Management of Kidney Allograft Dysfunction

Allograft dysfunction is a common problem after kidney transplant. Allograft rejection is an important entity, and timely diagnosis and appropriate treatment are essential for caring transplant recipients. Hyperacute rejection is mediated by the preformed donor specific antibody, while accelerated acute rejection represents an anamnestic response by memory B and T cells. They occur early after transplant. Acute cellular rejection is relatively common and usually responds to pulse corticosteroids or antithymocyte globulin (ATG). The complexity of antibody-mediated rejection (AMR) as well as its detrimental effect has been increasingly recognized. The treatment of acute AMR requires a combination of several modalities, such as plasmapheresis or immunoadsorption, IVIG, corticosteroids, rituximab and ATG. After treatment of rejection episode, the maintenance immunosuppressive drugs should be adjusted to prevent further acute rejection and/or evolution into chronic active rejection. Chronic rejection is not reversible and it has been recognized as the most important cause of chronic graft dysfunction and failure.

Impact of preformed donor-specific antibodies against HLA class Ⅰ on kidney graft outcomes:Comparative analysis of exclusively anti-Cw vs anti-A and/or-B antibodies

AIM To analyze the clinical impact of preformed antiH LA-Cw vs antiH LA-A and/or-B donor-specific antibodies(DSA) in kidney transplantation.METHODS Retrospective study, comparing 12 patients transplanted with DSA exclusively antiH LA-Cw with 23 patients with preformed DSA antiH LA-A and/or B.RESULTS One year after transplantation there were no differencesin terms of acute rejection between the two groups(3 and 6 cases, respectively in the DSA-Cw and the DSA-A-B groups; P = 1). At one year, eG FR was not significantly different between groups(median 59 mL /min in DSA-Cw group, compared to median 51 mL /min in DSA-A-B group, P = 0.192). Moreover, kidney graft survival was similar between groups at 5-years(100% in DSA-Cw group vs 91% in DSA-A-B group, P = 0.528). The sole independent predictor of antibody mediated rejection(AMR) incidence was DSA strength(HR = 1.07 per 1000 increase in MFI, P = 0.034). AMR was associated with shortened graft survival at 5-years, with 75% and 100% grafts surviving in patients with or without AMR, respectively(Log-rank P = 0.005).CONCLUSION Our data indicate that DSA-Cw are associated with an identical risk of AMR and impact on graft function in comparison with "classical" class I DSA.

Therapeutic apheresis in kidney transplantation: An updated review

Therapeutic apheresis is a cornerstone of therapy for several conditions in transplantation medicine and is available in different technical variants. In the setting of kidney transplantation, immunological barriers such as ABO blood group incompatibility and preformed donor-specific antibodies can complicate the outcome of deceased-or living-donor transplantation. Postoperatively,additional problems such as antibody-mediated rejection and a recurrence of primary focal segmental glomerulosclerosis can limit therapeutic success and decrease graft survival. Therapeutic apheresis techniques find application in these issues by separating and selectively removing exchanging or modifying pathogenic material from the patient by an extracorporeal aphaeresis system. The purpose of this review is to describe the available techniques of therapeutic aphaeresis with their specific advantages and disadvantages and examine the evidence supporting the application of therapeutic aphaeresis as an adjunctive therapeutic option to immunosuppressive agents in protocols before and after kidney transplantation.