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Leva vidareCostache, Camelia Teodora, Gazivoda, Svetlana January 2016 (has links)
Bakgrund: Organtransplantation ger nytt hopp och nytt liv till sjuka patienter. Njursvikt är en kronisk, försvagande sjukdom som påverkar många aspekter av patienternas liv. Den effektivaste behandlingen mot kronisk njursvikt är transplantation. Forskning visar hur patienterna upplever livet efter njurtransplantation.Syfte: Syftet är att sammanställa vetenskapliga artiklar som belyser patienters upplevelse av livet efter njurtransplantation.Metod: Litteraturstudie med tematisk analys av tio vetenskapliga artiklar med kvalitativ ansats.Resultat: Studiens resultat visade att en del av patienterna upplevde många positiva förändringar men det fanns också en del som upplevde ett antal begränsningar. Att leva med en ny njure ledde till en känsla av frihet, glädje, lycka och en möjlighet till att kunna planera mer långsiktigt. Rädsla och oro över att den nya njuren kunde stötas bort, skuld över att ta emot någon annans njure, livslångbehandling och för höga förväntningar ledde till ett begränsat liv. Resultatet visade inte på någon tydlig skillnad mellan kvinnor och mäns upplevelser av livet efter njurtransplantationen men vissa variationer kunde urskiljas.Konklusion: I studien framkom olika aspekter kring hur patienterna såg på livet efter en njurtransplantation. Före uppsatsen förväntade vi oss att patienterna skulle vara lättade då de tidigare varit på gränsen till döden. Men även om patienterna upplevde att de hade en högre livskvalitet efter transplantationen kom det ändå stunder då de misströstade och trodde att förbättringarna endast var tillfälliga. / Background: Organ transplantation gives new hope and new life to patients. Renal failure is a chronic, devastating disease that affects many aspects of the patients' lives. The most effective treatment for chronic kidney failure is transplantation. Research shows how patients experience life after kidney transplantationAim: The aim is to collect scientific articles that highlight the patient's experience of life after transplantation.Method: Literature study with thematic analysis of ten scientific articles with qualitative approach.Results: The study results showed that some of the patients experienced many positive changes, but there were also some who experienced a few limitations. Living with a new kidney led to a sense of freedom, joy, happiness, and opportunity to be able to plan more over a long term. The fear and concern that the new kidney could be rejected, guilt over receiving someone else's kidney, life-long treatment and high expectations led to a limited life. The results showed no significant difference between women’s and men's experiences of life after kidney transplantation, but certain variations could be discerned.Conclusion: The study revealed different aspects of the experience of life after renal transplantation. Before this study was expected only the good aspects and believed that it would only be a relief for patients as the previously lasted on the verge of death. Even if patients feel that they had a better life than before the transplant there are times when they despair, and think that the improvements they experience only temporary.
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The Role of Genetic Variant and Genomic Features in Outcomes Following TransplantationWang, Yiwen 07 September 2022 (has links)
No description available.
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Predictive Value of HAS-BLED Score Regarding Bleeding Events and Graft Survival following Renal TransplantationHau, Hans Michael, Eckert, Markus, Laudi, Sven, Völker, Maria Theresa, Stehr, Sebastian, Rademacher, Sebastian, Seehofer, Daniel, Sucher, Robert, Piegeler, Tobias, Jahn, Nora 02 November 2023 (has links)
Objective: Due to the high prevalence and incidence of cardio- and cerebrovascular diseases
among dialysis-dependent patients with end-stage renal disease (ERSD) scheduled for kidney
transplantation (KT), the use of antiplatelet therapy (APT) and/or anticoagulant drugs in this patient
population is common. However, these patients share a high risk of complications, either due to
thromboembolic or bleeding events, which makes adequate peri- and post-transplant anticoagulation
management challenging. Predictive clinical models, such as the HAS-BLED score developed for
predicting major bleeding events in patients under anticoagulation therapy, could be helpful tools for
the optimization of antithrombotic management and could reduce peri- and postoperative morbidity
and mortality. Methods: Data from 204 patients undergoing kidney transplantation (KT) between
2011 and 2018 at the University Hospital Leipzig were retrospectively analyzed. Patients were
stratified and categorized postoperatively into the prophylaxis group (group A)—patients without
pretransplant anticoagulation/antiplatelet therapy and receiving postoperative heparin in prophylactic
doses—and into the (sub)therapeutic group (group B)—patients with postoperative continued
use of pretransplant antithrombotic medication used (sub)therapeutically. The primary outcome
was the incidence of postoperative bleeding events, which was evaluated for a possible association
with the use of antithrombotic therapy. Secondary analyses were conducted for the associations of
other potential risk factors, specifically the HAS-BLED score, with allograft outcome. Univariate and
multivariate logistic regression as well as a Cox proportional hazard model were used to identify risk
factors for long-term allograft function, outcome and survival. The calibration and prognostic accuracy
of the risk models were evaluated using the Hosmer–Lemshow test (HLT) and the area under
the receiver operating characteristic curve (AUC) model. Results: In total, 94 of 204 (47%) patients received
(sub)therapeutic antithrombotic therapy after transplantation and 108 (53%) patients received
prophylactic antithrombotic therapy. A total of 61 (29%) patients showed signs of postoperative
bleeding. The incidence (p < 0.01) and timepoint of bleeding (p < 0.01) varied significantly between
the different antithrombotic treatment groups. After applying multivariate analyses, pre-existing
cardiovascular disease (CVD) (OR 2.89 (95% CI: 1.02–8.21); p = 0.04), procedure-specific complications
(blood loss (OR 1.03 (95% CI: 1.0–1.05); p = 0.014), Clavien–Dindo classification > grade II (OR 1.03
(95% CI: 1.0–1.05); p = 0.018)), HAS-BLED score (OR 1.49 (95% CI: 1.08–2.07); p = 0.018), vit K antagonists
(VKA) (OR 5.89 (95% CI: 1.10–31.28); p = 0.037), the combination of APT and therapeutic
heparin (OR 5.44 (95% CI: 1.33–22.31); p = 0.018) as well as postoperative therapeutic heparin (OR 3.37
(95% CI: 1.37–8.26); p < 0.01) were independently associated with an increased risk for bleeding. The
intraoperative use of heparin, prior antiplatelet therapy and APT in combination with prophylactic heparin was not associated with increased bleeding risk. Higher recipient body mass index (BMI)
(OR 0.32 per 10 kg/m2 increase in BMI (95% CI: 0.12–0.91); p = 0.023) as well as living donor KT
(OR 0.43 (95% CI: 0.18–0.94); p = 0.036) were associated with a decreased risk for bleeding. Regarding
bleeding events and graft failure, the HAS-BLED risk model demonstrated good calibration (bleeding
and graft failure: HLT: chi-square: 4.572, p = 0.802, versus chi-square: 6.52, p = 0.18, respectively) and
moderate predictive performance (bleeding AUC: 0.72 (0.63–0.79); graft failure: AUC: 0.7 (0.6–0.78)).
Conclusions: In our current study, we could demonstrate the HAS-BLED risk score as a helpful tool
with acceptable predictive accuracy regarding bleeding events and graft failure following KT. The
intensified monitoring and precise stratification/assessment of bleeding risk factors may be helpful
in identifying patients at higher risks of bleeding, improved individualized anticoagulation decisions
and choices of antithrombotic therapy in order to optimize outcome after kidney transplantation
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The Value of Graft Implantation Sequence in Simultaneous Pancreas-Kidney Transplantation on the Outcome and Graft SurvivalHau, Hans-Michael, Jahn, Nora, Rademacher, Sebastian, Sucher, Elisabeth, Babel, Jonas, Mehdorn, Matthias, Lederer, Andri, Seehofer, Daniel, Scheuermann, Uwe, Sucher, Robert 04 May 2023 (has links)
Background/Objectives: The sequence of graft implantation in simultaneous pancreas-kidney transplantation (SPKT) warrants additional study and more targeted focus, since little is known about the short- and long-term effects on the outcome and graft survival after transplantation. Material and methods: 103 patients receiving SPKT in our department between 1999 and 2015 were included in the study. Patients were divided according to the sequence of graft implantation into pancreas-first (PF, n = 61) and kidney-first (KF, n = 42) groups. Clinicopathological characteristics, outcome and survival were reviewed retrospectively. Results: Donor and recipient characteristics were similar. Rates of post-operative complications and graft dysfunction were significantly higher in the PF group compared with the KF group (episodes of acute rejection within the first year after SPKT: 11 (18%) versus 2 (4.8%); graft pancreatitis: 18 (18%) versus 2 (4.8%), p = 0.04; vascular thrombosis of the pancreas: 9 (14.8%) versus 1 (2.4%), p = 0.03; and delayed graft function of the kidney: 12 (19.6%) versus 2 (4.8%), p = 0.019). The three-month pancreas graft survival was significantly higher in the KF group (PF: 77% versus KF: 92.1%; p = 0.037). No significant difference was observed in pancreas graft survival five years after transplantation (PF: 71.6% versus KF: 84.8%; p = 0.104). Kidney graft survival was similar between the two groups. Multivariate analysis revealed order of graft implantation as an independent prognostic factor for graft survival three months after SPKT (HR 2.6, 1.3–17.1, p = 0.026) and five years (HR 3.7, 2.1–23.4, p = 0.040). Conclusion: Our data indicates that implantation of the pancreas prior to the kidney during SPKT has an influence especially on the early-post-operative outcome and survival rate of pancreas grafts.
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Bayesian Filtering for Personalized Kidney Graft Risk PredictionMsinda, Maoni Ngowa January 2024 (has links)
Accurately predicting graft failure following kidney transplantation is essential for identifying high-risk patients and tailoring treatment strategies. This thesis aims to forecast kidney graft failure by estimating and predicting the glomerular filtration rate (GFR) using real data related to pre-transplant and post-operative patients status, provided to us by Hannover Medical School. To achieve this, we implement three Bayesian filtering techniques: the Extended Kalman Filter (EKF), the Unscented Kalman Filter (UKF), and the Particle Filter (PF), on a discrete-time state-space stochastic Duffing oscillator model. We also conduct regression analysis between available GFR measurements and the filters' estimated and predicted values, followed by an error analysis using root mean square error. Our results demonstrate that Particle Filter, utilizing 10,000 particles, consistently produced accurate estimates compared to other filters in most patients. Furthermore, we observe that data interpolation yields more accurate results.
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The Role of Innate Immune Cells in the Prediction of Early Renal Allograft Injury Following Kidney TransplantationJahn, Nora, Sack, Ulrich, Stehr, Sebastian, Vöelker, Maria Theresa, Laudi, Sven, Seehofer, Daniel, Atay, Selim, Zgoura, Panagiota, Viebahn, Richard, Boldt, Andreas, Hau, Hans-Michael 31 July 2024 (has links)
Background: Despite recent advances and refinements in perioperative management of kidney transplantation (KT), early renal graft injury (eRGI) remains a critical problem with serious impairment of graft function as well as short- and long-term outcome. Serial monitoring of peripheral blood innate immune cells might be a useful tool in predicting post-transplant eRGI and graft outcome after KT. Methods: In this prospective study, medical data of 50 consecutive patients undergoing KT at the University Hospital of Leipzig were analyzed starting at the day of KT until day 10 after the transplantation. The main outcome parameter was the occurrence of eRGI and other outcome parameters associated with graft function/outcome. eRGI was defined as graft-related complications and clinical signs of renal IRI (ischemia reperfusion injury), such as acute tubular necrosis (ATN), delayed graft function (DGF), initial nonfunction (INF) and graft rejection within 3 months following KT. Typical innate immune cells including neutrophils, natural killer (NK) cells, monocytes, basophils and dendritic cells (myeloid, plasmacytoid) were measured in all patients in peripheral blood at day 0, 1, 3, 7 and 10 after the transplantation. Receiver operating characteristics (ROC) curves were performed to assess their predictive value for eRGI. Cutoff levels were calculated with the Youden index. Significant diagnostic immunological cutoffs and other prognostic clinical factors were tested in a multivariate logistic regression model. Results: Of the 50 included patients, 23 patients developed eRGI. Mean levels of neutrophils and monocytes were significantly higher on most days in the eRGI group compared to the non-eRGI group after transplantation, whereas a significant decrease in NK cell count, basophil levels and DC counts could be found between baseline and postoperative course. ROC analysis indicated that monocytes levels on POD 7 (AUC: 0.91) and NK cell levels on POD 7 (AUC: 0.92) were highly predictive for eRGI after KT. Multivariable analysis identified recipient age (OR 1.53 (95% CI: 1.003–2.350), p = 0.040), recipient body mass index > 25 kg/m2 (OR 5.6 (95% CI: 1.36–23.9), p = 0.015), recipient cardiovascular disease (OR 8.17 (95% CI: 1.28–52.16), p = 0.026), donor age (OR 1.068 (95% CI: 1.011–1.128), p = 0.027), <0.010), deceased-donor transplantation (OR 2.18 (95% CI: 1.091–4.112), p = 0.027) and cold ischemia time (CIT) of the renal graft (OR 1.005 (95% CI: 1.001–1.01), p = 0.019) as clinically relevant prognostic factors associated with increased eRGI following KT. Further, neutrophils > 9.4 × 103/μL on POD 7 (OR 16.1 (95% CI: 1.31–195.6), p = 0.031), monocytes > 1150 cells/ul on POD 7 (OR 7.81 (95% CI: 1.97–63.18), p = 0.048), NK cells < 125 cells/μL on POD 3 (OR 6.97 (95% CI: 3.81–12.7), p < 0.01), basophils < 18.1 cells/μL on POD 10 (OR 3.45 (95% CI: 1.37–12.3), p = 0.02) and mDC < 4.7 cells/μL on POD 7 (OR 11.68 (95% CI: 1.85–73.4), p < 0.01) were revealed as independent biochemical predictive variables for eRGI after KT. Conclusions: We show that the combined measurement of immunological innate variables (NK cells and monocytes on POD 7) and specific clinical factors such as prolonged CIT, increased donor and recipient age and morbidity together with deceased-donor transplantation were significant and specific predictors of eRGI following KT. We suggest that intensified monitoring of these parameters might be a helpful clinical tool in identifying patients at a higher risk of postoperative complication after KT and may therefore help to detect and—by diligent clinical management—even prevent deteriorated outcome due to IRI and eRGI after KT.
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Modulating T Cell costimulation to prevent renal allograft rejection in nonhuman primatesSong, Lijun 08 1900 (has links)
La transplantation d'organes est souvent la meilleure approche thérapeutique pour l'insuffisance organique au stade terminal. Le rejet de greffe est le principal obstacle pour une transplantation réussie, car cette dernière est le plus fréquemment réalisée entre individus génétiquement distincts. Les tissus ou organes transplantés sont généralement reconnus par le système immunitaire comme corps étrangers et sont rapidement détruits. Une série d'approches a été réalisée en clinique pour augmenter l'acceptation de la transplantation d’organes. Les immunosuppresseurs ont un rôle clé dans le combat contre le rejet de greffe. Actuellement, les résultats à court terme de la transplantation d'organes ont été considérablement améliorés avec l'émergence des inhibiteurs de la calcineurine (ICN), mais les résultats à long terme sont encore insatisfaisants. L'une des principales raisons est que les médicaments immunosuppresseurs actuels manquent de spécificité. Ces agents, en particulier ICN, sont considérés comme les facteurs de risque pour la perte tardive du greffon et les décès avec un greffon fonctionnel en raison de la toxicité des médicaments, de la sur-immunosuppression et d'autres effets secondaires. Ainsi, il y a un besoin urgent de rechercher de nouvelles thérapies idéales.
Les lymphocytes T jouent un rôle central dans l'initiation du rejet des allogreffes. La pleine activation des cellules T nécessite au moins deux signaux combinés, mais distincts. En plus du signal généré par l'interaction entre le récepteur des cellules T (TCR) et les complexes CMH-peptides, le second signal, appelé signal de costimulation qui est délivré par l'engagement du récepteur de costimulation avec son ligand, est essentiel. L'engagement du TCR en l'absence de signaux de costimulation peut donner lieu à l'anergie des cellules T, un état d'absence de réponse immunitaire. Les molécules costimulatrices acquièrent ainsi l'attention en tant que cibles thérapeutiques potentielles. Du fait que ces molécules soient largement limitées à des cellules T et/ou des cellules présentatrices d'antigène, cibler la voie de signalisation de costimulation offre la possibilité de moduler le système immunitaire d'une manière plus sélective par rapport à des agents immunosuppresseurs conventionnels.
À ce jour, de nombreuses molécules costimulatrices ont été identifiées et certaines ont été testées en tant que cibles thérapeutiques dans des modèles de transplantation d'organes. Les axes CD28–CD80/86 et CD40–CD40L sont importants et les deux voies de signalisation de costimulation les mieux connues. Bélatacept est un variant de l'antigène 4 des lymphocytes T cytotoxiques-immunoglobuline G (CTLA4-Ig) qui bloque la voie de signalisation CD28–CD80/86. C'est le seul bloqueur de la costimulation à être approuvé pour utilisation clinique en transplantation d'organes. Par rapport à la thérapie basée sur les ICN pour les receveurs de transplantation rénale, les thérapies à base de bélatacept montrent un taux similaire de survie, une fonction supérieure du greffon et l'amélioration du profil de risque cardiovasculaire. Cependant, bélatacept est également associée à des taux plus élevés de rejet aigu et de syndrome lymphoprolifératif post-greffe (SLPG).
Dans notre étude, l'efficacité d'ASKP1240, un nouvel AcM anti-CD40 complètement humain qui bloque la voie de costimulation CD40–CD40L, a été évaluée sur la prévention du rejet d'allogreffe avec le modèle de transplantation rénale chez le singe cynomolgus. Quand ASKP1240 a été administré seul, il a réduit l'incidence du rejet aigu et a prolongé la survie de l'allogreffe rénale dépendamment de la dose administrée. L'acceptation de l'allogreffe rénale a été encore améliorée chez des singes qui ont reçus des traitements d'ASKP1240 combiné avec le tacrolimus (dose sub-thérapeutique) ou le mycophénolate mofétil (MMF). Le rejet aigu d'allogreffe a été totalement éliminé chez ces animaux et la médiane de survie du greffon rénal de ces groupes était significativement plus longue que ceux des groupes avec un traitement monothérapie. ASKP1240 a été bien toléré pour un traitement allant jusqu'à 180 jours. Il n'y avait pas d'effets secondaires évidents, y compris les complications thromboémboliques liées au médicament. L'administration d'ASKP1240 n'a pas induite de libération de cytokines.
Ensuite, nous avons étudié les effets d'ASP2409 sur le rejet de l'allogreffe rénale et la survie chez des singes cynomolgus. ASP2409 est une nouvelle CD86-sélective variante de CTLA4-Ig, qui possède une affinité de liaison au CD86 14 fois plus élevée que le bélatacept in vitro et une amélioration de la puissance immunosuppressive. Une haute dose d'ASP2409 en monothérapie a montré des résultats supérieurs dans la réduction de rejet aigu et la prolongation de la survie de l'allogreffe rénale en comparaison avec une faible dose d'ASP2409 en monothérapie. Une faible dose d'ASP2409 en combinaison avec tacrolimus (dose sub-thérapeutique) inhibe complètement le rejet aigu d'allogreffe et prolonge significativement la survie de l'allogreffe rénale par rapport à une monothérapie avec une faible dose d'ASP2409 ou une dose sub-thérapeutique de tacrolimus. La médiane de survie de l'allogreffe des animaux recevant un traitement à base d'une dose élevée d'ASP2409, bélatacept, ou une dose thérapeutique de tacrolimus étaient identiques (> 91 jours). Les traitements à base d'une dose élevée d'ASP2409 présentaient de meilleurs résultats histopathologiques que le traitement à base de bélatacept. En outre, la fréquence des cellules FoxP3+ dans les allogreffes rénales a été observée plus haute dans les traitements à base d'ASP2409 et de bélatacept comparés aux traitements à base de tacrolimus. L'étude a également montré que ASP2409 est sans danger pour les animaux pour les doses qui ont été testées. Nous n'avons pas trouvé de graves effets secondaires liés à ASP2409 au cours des 91 jours d'étude.
Collectivement, ces résultats suggèrent que la modulation sélective de la costimulation des cellules T avec des bloqueurs de la costimulation est une stratégie réalisable pour la prévention et le traitement du rejet d'allogreffe. ASKP1240 et ASP2409 sont tous deux des agents immunosuppresseurs prometteurs pour les régimes d'évitement ou de réduction des inhibiteurs de la calcineurine. / Organ transplantation is often the best therapeutic approach for end-stage organ failure. Graft rejection is the major obstacle to successful transplantation because transplantation is most frequently carried out between genetically distinct individuals. Transplanted tissues or organs are usually recognized by the immune system as foreign and are rapidly destructed without immune interventions. A series of approaches have thus been applied in clinic to inhibit the allogenic immune responses and in turn increase organ transplant acceptance. Immunosuppressive drugs are the key players in the "war" against immune cell-mediated rejection of allogenic transplants. Currently, the use of calcineurin inhibitors (CNIs) has dramatically decreased the risk of acute transplant rejection and improved the short-term outcomes of organ transplantation, but the long-term outcomes are still unsatisfied. One of the main reasons causing unsatisfied long-term outcomes is that current immunosuppressive drugs do not specifically target immune cells that cause transplant rejection. These immunosuppressive agents, especially CNIs, are the risk factors for late graft loss and death with functioning graft (DWFG) due to drug toxicity, over-immunosuppression, and other side-effects. Thus there is an urgent need for seeking novel therapies that can selectively eliminate the alloreactive immune responses while preserving the integrity of the remainder of the host immune system.
It has been known that T cells play a central role in initiating allograft rejection. Full activation of T cells requires at least two collaborative but distinct signals. The first signal is generated by the interaction between T cell receptor (TCR) and MHC-peptide complex. The second signal, termed costimulatory signal, is delivered through the engagement of costimulatory receptors by their ligands. Importantly, TCR engagement in the absence of costimulatory signals can result in T cell anergy, a state of T cell unresponsiveness. Costimulatory molecules thus gain attention as potential therapeutic targets. Because these molecules are primary expressed on T cells and/or antigen-presenting cells, targeting costimulatory signaling pathway offers the oppertumities to modulate immune system in a more selective way relative to conventional immunosuppressive agents.
To date, numerous costimulatory molecules have been identified and some have been tested as therapeutic targets in organ transplant models. CD28–CD80/86 and CD40–CD40L axis are two important and the most well known costimulatory signaling pathways. Belatacept, a variant of cytotoxic T lymphocyte antigen 4-immunoglobulin G (CTLA4-Ig) that blocks CD28–CD80/86 signaling pathway, is the only costimulation blocker to be approved for clinical use in organ transplantation. Compared to CNI-based regimen for kidney transplant recipients, belatacept-based regimens show similar patient and graft survival rate, superior graft function, and improved cardiovascular risk profile. However, belatacept is also associated with higher rates of acute rejection and posttransplant lymphoproliferative disorder (PTLD). Disruption of CD40–CD40L interaction with anti-CD40L mAbs has also been demonstrated to be a reliable approach for preventing acute rejection and for prolonging allograft survival. Unfortunately, unexpected thromboembolic complications in preclinical studies and clinical trials discontinued the development of anti-CD40L mAbs. The main objective of this thesis is to identify the optimal T cell costimulation blockers that can show improved safety and non-inferior efficacy in promoting allograft acceptance relative to current costimulatory blocking agents.
Anti-CD40 mAbs are an alternative approach to block CD40–CD40L costimulatory pathway. CD40 is not involved in the stability of platelet thrombi and anti-CD40 mAbs are expected to not cause thromboembolic events. ASKP1240 is a novel fully human anti-CD40 mAb. In this study, the efficacy of ASKP1240 in the prevention of renal allograft rejection was evaluated in cynomolgus monkey kidney transplantation model. When ASKP1240 was administered alone, it dose-dependently reduced the incidence of acute rejection and prolonged renal allograft survival. Renal allograft acceptance was further improved in the monkey which received regiments using ASKP1240 combined with conventional immunosuppressive drugs tacrolimus (sub-therapeutic dose) or mycophenolate mofetil (MMF). Acute allograft rejection was totally eliminated in these animals and the kidney allograft median survival times (MST) of these groups were significantly longer than those of monotherapy groups. ASKP1240 administration did not induce cytokine release. This agent was well tolerated in monkey kidney transplant recipients during the 180-day treatment period. There were no obvious side effects including drug-related thromboembolic complications.
Next, we tested the hypothesis that a CD86-selective variant of CTLA4-Ig might show non-inferior efficacy on the prevention of allograft rejection and prolongation of graft survival in comparison with belatacept. CD86 is the dominating ligand between the two natural ligands for CD28 in alloimmune response. Improvements in CD86 binding affinity of CTLA4-Igs confer increased immunosuppressive potency. A CD86-selective CTLA4-Ig variant may reach therapeutic levels of CD86 occupancy while occupies substantially less CD80 ligand than non-CD86-selective CTLA4-Igs. Preservation of CD80 signaling may be favoring to retain protective immunity and to improve safety of CTLA4-Ig therapy. This thesis investigated the effects of a novel CD86-selective CTLA4-Ig variant, ASP2409, on renal allograft rejection and survival in cynomolgus monkeys. ASP2409 possesses 14-fold higher in vitro CD86 binding affinity than belatacept and improved immunosuppressive potency. Compared to no-treatment control, low-dose (0.3 mg/kg) ASP2409 monotherapy significantly prolonged renal allograft survival (MST = 5 and 26 days, respectively) but did not decrease the incidence of acute rejection (8/8). The rate of acute renal allograft rejection was reduced in the group of high-dose ASP2409 monotherapy (2/7) and, correspondingly, a much longer MST (>91 days) was shown in this group. Combination therapy of low-dose ASP2409 and tacrolimus (sub-therapeutic dose) completely eliminated acute allograft rejection and notably prolonged renal allograft survival (MST >91 days). The MSTs of renal allografts in the animals receiving high-dose ASP2409-, belatacept-, and therapeutic dose tacrolimus-based immunosuppressive regimens were same (>91 days). High-dose ASP2409-based regimens exhibited better histopathological results than belatacept-based regimen. Furthermore, higher frequencies of FoxP3+ Tregs in renal allografts were observed in ASP2409- and belatacept-based regimens compared to tacrolimus-based regimen. ASP2409 was also demonstrated to be safe for animals with the doses to be tested. There were no serious side effects related to ASP2409 to be found in term of 91-day study.
This study demonstrates that ASKP1240 is as effective as anti-CD40L mAbs on inhibition of acute rejection and prolongation of renal allograft survival, and do not cause thromboembolic complications. Previous studies indicated that CNIs could diminish the effects of anti-CD40L mAbs. In our study, ASKP1240 in combination with tacrolimus or MMF shows improved efficiency. Furthermore, the effects of ASP2409 on promoting renal allograft acceptance are not inferior to belatacept. These results collectively suggest that ASKP1240 and ASP2409 both are the promising immunosuppressive agents for solid organ transplantation.
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Učestalost, vrsta i lokalizacija premalignih i malignih lezija kože kod bolesnika nakon transplantacije bubrega / Frequency, type and localization of premalignant and malignant skin lesions in renal transplant recipientsRoš Tatjana 27 September 2016 (has links)
<p>Osobe kojima su transplantirani organi imaju povećan rizik pojave malignih oboljenja, među kojima dominiraju maligni tumori kože. Smatra se da je osnovni razlog primena imunosupresivne terapije, ali još nije sasvim jasan mehanizam i nivo dejstva različitih imunosupresiva. Važan uticaj na nastanak većine malignih tumora kože ima ultraljubičasto (UV) zračenje koje izaziva pojačano starenje kože u vidu histološki prepoznatljivog fotooštećenja, sa odlikama razvoja elastoze i limfocitne infiltracije. U našoj zemlji do sada nisu sprovođena istraživanja rizika pojave maligniteta kože kod transplantiranih pacijenata, ne postoje podaci o njihovoj incidenci, uticaju imunosupresivne terapije i drugim potencijalnim faktorima rizika. U dostupnoj literaturi nema objavljenih radova iz oblasti analize histološkog fotooštećenja kože kod osoba na imunosupresivnoj terapiji. Ciljevi ove studije preseka bili su utvrđivanje učestalosti, vrste i lokalizacije premalignih i malignih lezija kože kod pacijenata nakon transplantacije bubrega, povezanosti njihove pojave sa dužinom, vrstom i režimom primene imunosupresivne terapije i sa histološki verifikovanim fotooštećenjem perilezionalne kože. U studiju je uključeno 66 pacijenata kojima je transplantiran bubreg (primaoci organskog transplantata – POT). Relevantni podaci su prikupljeni putem upitnika i iz medicinske dokumentacije, kliničko-dermoskopskim pregledom kože uočene suspektne lezije su bioptirane u cilju postavljanja dijagnoze i utvrđivanja histoloških parametara fotooštećenja, a u studiju su uključeni i maligni tumori kože POT ispitanika uklonjeni u periodu od prethodnih 5 godina ali nakon transplantacije. Radi komparacije prisutnih faktora rizika i stepena fotooštećenja kože sa opštom populacijom formirana je kontrolna grupa (KG) ispitanika kojima je prethodno bioptirana koža, bez oboljenja bubrega i bez imunosupresije, slična po polu i životnoj dobi sa onim POT ispitanicima kojima je urađena biopsija. Za svaku leziju iz POT grupe obezbeđene su po 2 lezije iz KG, tako da je pojedinim ispitanicima POT grupe analizirano više lezija, dok je u KG 1 ispitanik – 1 lezija. Osnovno oboljenje bubrega do započinjanja dijalize kod ispitanika POT grupe prosečno je trajalo 7,67 godina, u strukturi oboljenja bubrega dominirao je hronični glomerulonefritis sa 31,8%, a ispitanici su na dijalizi bili prosečno 4,54 godine. Prosečna životna dob ispitanika u momentu transplantacije iznosila je 42,5 godina, 60,6% imalo je isključivo kadaveričnu transplantaciju, a prosečno trajanje jatrogene imunosupresije iznosilo je 4,89 god. U POT grupi bioptirane su 33 lezije, među kojima su od značaja za studiju bile 2 (6,1%) aktinične keratoze (AK), 3 (9,1%) displastična nevusa (DN), 1 (3,0%) melanom (MM), 3 (9,1%) skvamocelularna karcinoma (SCK) i 6 (18,2%) bazocelularnih karcinoma (BCK). U POT grupi učestalost MM bila je 1,5%, učestalost SCK 4,5%, učestalost BCK 9,1%, dok je utvrđeni relativan rizik pojave MM u POT populaciji 227 puta veći, BCK 316 puta veći, a SCK 805 puta veći nego u opštoj populaciji. Relativan rizik nastanka AK i DN nije određen zbog izostanka zvanične registracije u opštoj populaciji. POT grupa i KG nisu se statistički značajno razlikovale po Ficpatrikovom fototipu kože, profesionalnoj izloženosti UV zračenju, upotrebi solarijuma, broju solarnih opekotina, ličnoj anamnezi malignih tumora kože i konzumiranju cigareta. Pripadnici KG su se značajno više rekreativno izlagali UV zračenju, češće koristili sredstva za zaštitu od sunčevog zračenja, češće imali bliske srodnike sa malignim tumorima kože, češće konzumirali alkohol, značajno veći broj ispitanika KG imao je pregled kompletne kože i informaciju o merama prevencije od strane lekara, dok 50% ispitanika POT grupe nije znalo da su pod povećanim rizikom pojave maligniteta kože. U stepenu elastoze među grupama nije postojala statistički značajna razlika, dok je limfocitna infiltracija bila marginalno izrazitija u POT grupi bez obzira na vrstu lezije. U POT grupi utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom perilezionalne limfocitne infiltracije i elastoze. U KG utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom limfocitne infiltracije, dok nije bilo statistički značajne razlike u stepenu perilezionalne elastoze. U studiji je utvrđeno da osobe nakon transplantacije bubrega imaju statistički značajno veći rizik nastanka BCK, SCK i MM kože u odnosu na opštu populaciju, sa najčešćom lokalizacijom ovih tumora u predelu glave. Dužina primene imunosupresivne terapije uopšteno nije statistički značajno uticala na pojavu premalignih i malignih tumora kože, ali je kumulativna doza pojedinih imunosupresiva poput ciklosporina i azatioprina imala statistički značajan uticaj na pojavu premalignih i malignih lezija kože. Dužina imunosupresije je statistički značajno uticala na stepen elastoze, ali je imala marginalan uticaj na stepen perilezionalne limfocitne infiltracije.</p> / <p>Organ transplant recipients are at an increased risk of developing malignancies, with the predominance of malignant skin tumors. The main cause is considered to be the administration of immunosuppressive therapy, but the mechanism and effect levels of different immunosuppressive agents are still not completely clear. Ultraviolet (UV) rays also influence the development of malignant skin tumors, causing increased skin aging with histologically recognisable photo damage, with its hallmark being development of elastosis and lymphocytic infiltration. No research on the topic of risks of malignant skin tumors in transplant patients has been done in our country, there is no data on their incidence, or on the effects of immunosuppressive agents and other potential risk factors. There are also no published studies in the field of hystological photo damage analysis in patients on immunosuppressive therapy. The aims of this study were to establish the rates of occurance, types and localisation of premalignant and malignant skin lesions in kidney transplant recipients (KTR) and to associate their advent with the length, type and regimen of immunosuppressive therapy. A total of 66 KTR patients were enrolled in the study. Relevant information was gathered through a specially constructed questionnaire and from the medical records, followed by combined clinical and dermoscopic skin examination to detect suspicious lesions which were biopsied in order to determine the histopathologic diagnosis of the lesion and perilesional degree of photo damage. The study also encompassed malignant skin tumors of KTR patients that have been removed in the last 5 years, but after the transplantation. For the sake of comparison of the risk factors and the levels of photo damage with the general population, an age and sex - matched control group (CG) of patients with previous skin biopsy but without kidney disease and immunosuppression was formed. For each lesion from KTR group, 2 lesions from CG were provided, meaning that some KTR patients had several lesions analysed, whereas in the CG only 1 lesion per patient was analyzed. The average duration of underlying kidney diseases in KTR was 7,67 years, the most frequent being chronic glomerulonephritis (31,8%), and an average duration of dialysis was 4,54 years. The mean age at transplantation was 42,5 years, with 60,6% of the KTR having exclusively cadaveric graft. The mean duration of the iatrogenic immunosuppression was 4,89 years. In the KTR group a total of 33 lesions were biopsied, 2 of which were actinic keratoses (AK) (6,1%), 3 were dysplastic nevi (DN) (9,1%), 1 melanoma (MM) (3,0%), 3 squamous cell carcinomas (SCC) (9,1%) and 6 basal cell carcinomas (BCC) (18,2%). The estimated frequency of MM was 1,5%, SCC 4,5%, BCC 9,1%, and the estimated relative risk of MM in KTR being 227, BCC 316, and SCC 805 times higher compared to the general population. The relative risk of AK and DN development could not have been estimated as there are no official records in the general population. The KTR and CG were not significantly different judging by the Fitzpatrick skin phototype, occupational UV exposure, sunbed usage, personal history of skin cancers, or smoking. The controls were recreationally more exposed to UV rays, used sun protective measures more frequently, had more relatives with skin cancers and consumed alcohol more frequently. A significantly greater number of controls had had complete skin examination and protective measures counceling by the doctor, while 50% of KTR patients did not even know that they were at an increased risk of malignant skin tumor development. There was no significant difference in elastosis levels among the groups, whereas the lymphocitic infiltration was only marginally greater in the KTR group. A significant association between the level of perilesional photodamage and developement of malignant tumors was estimated for the KTR group, whereas in the CG only the perilesional lymphocitic infiltration was strongly associated to malignant lesions. The study results suggest that KTR patients have a significantly higher risk of BCC, SCC and MM development in comparison with the general population, the most common localisation being in the head region. The duration of the immunosuppressive therapy had no significant effect on the premalignant and malignant tumors development, whereas the cummulative dose of certain immunosuppressives (such as cyclosporine and azathioprine) affected the development notably. The duration of immunosuppression statistically influenced the elastosis levels, but had only a marginal influence on the perilesional lymphocitic infiltration levels.</p>
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Humorální rejekce po transplantaci ledviny a vyšetřování protilátek proti HLA a non-HLA antigenům. / Humoral rejection after kidney transplantation and monitoring antibodies against HLA and non-HLA antigens.Valhová, Šárka January 2013 (has links)
Kidney transplantation is the treatment of choice for patients with end stage renal failure and is associated with prolonged survival of patients and better quality of life than long-term dialysis. Simultaneously, however, transplantation carries the risk of immunological complications leading to graft rejection. A serious problem in patients after organ transplantation is the development of humoral rejection, which is most often associated with the presence of antibodies specific to HLA antigens, particularly against mismatched HLA antigens of the organ donor. In certain cases antibodies may be specific to antigens expressed on endothelial cells, not on lymphocytes, like MICA, MICB, ICAM, and up till now unidentified tissue-specific antigens. Humoral rejection has significantly worse prognosis for the transplanted kidney than cellular rejection, and therefore its timely diagnosis is of great importance for the subsequent choice of appropriate therapy. The diagnosis of humoral rejection is based on the simultaneous detection of C4d deposits in the peritubular capillaries of the transplanted kidney and the finding of antibodies specific to the mismatched antigens of the donor (donor specific antibodies, DSA). The aim of our retrospective study was to contribute to improvement of the diagnosis of acute and...
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Análise da doença óssea após o transplante renal estável: elevada prevalência de doença mista / Bone status after second year of stable graft function: a mixed bone diseaseNeves, Carolina Lara 19 September 2007 (has links)
Introdução: Os corticosteróides e a persistência do hiperparatiroidismo são os principais fatores envolvidos na perda de massa óssea de pacientes ao longo do primeiro ano de transplante renal (TR).Os estudos no TR tardio são muito contraditórios,uma vez que as populações avaliadas foram heterogêneas.Os resultados revelaram diminuição da formação e aumento da reabsorção óssea além de defeito na mineralização. Objetivos: 1) Avaliar o metabolismo mineral e o tecido ósseo após o segundo ano de transplante renal em pacientes com boa função do enxerto e sem fatores de risco para a perda de massa óssea. 2) Determinar os possíveis fatores determinantes da massa e remodelação óssea. 3) Estudar a atividade funcional dos osteoblastos in vitro. Métodos: Avaliamos 27 pacientes transplantados renais com idade entre 18 a 50 anos (36,4 + 8,9 anos) boa função do enxerto (clearance de creatinina > 50ml/min), recebendo o mesmo esquema imunossupressor desde o início do TR e doses mínimas de corticosteróides. Todos apresentavam função gonadal normal. Excluímos os pacientes submetidos a paratiroidectomia, que receberam tratamento prévio com cálcio, vitamina D ou bisfosfonato. Os pacientes foram submetidos a avaliação clínica, laboratorial, densitometria óssea (DO) e biópsia óssea da crista ilíaca. Foi realizado cultura de células de osteoblastos, obtidos da biópsia óssea, e analisada a taxa de proliferação celular e expressão de fosfatase alcalina. Resultados: A hipercalcemia esteve presente em 40% dos pacientes, hipofosfatemia em 26% e 15% apresentavam acidose metabólica. Nos pacientes em uso de tacrolimus (FK) os níveis de fósforo sérico foram significativamente inferiores aos do grupo ciclosporina (CSA) (p=0.019). Os níveis de PTH estavam adequados para a função renal na maioria dos pacientes, entretanto 30% tinham níveis superiores a 65 pg/ml. Os níveis de osteoprotegerina (OPG) (85%) e deoxipiridinolina (DPD) (95%) estavam elevados na maioria dos pacientes Quanto aos valores de 25(OH) D (25,4 ± 8,7 ng/ml) os mesmos encontravam-se reduzidos em 63% dos pacientes. Não houve perda óssea significativa pela análise do score Z lombar (-0,9 ± 1,5) e do femur (-0,8 ± 1,1), porém em 26% dos pacientes diagnosticamos osteoporose pela densitometria. A média do volume ósseo estava dentro da normalidade, porém, 30% dos pacientes apresentavam redução do BV/TV. Nossos pacientes tinham aumento da separação e diminuição do número das trabéculas ósseas, além de aumento das superfícies osteóide, osteoblástica, de reabsorção e osteoclástica. Em cerca de 60% dos pacientes observamos diminuição da taxa de formação óssea e em 85% deles da superfície mineralizante. Retardo na mineralização óssea foi observado em 46% dos pacientes. Insuficiência de 25(OH) D cursou com defeito de mineralização em todos os pacientes. Os osteoblastos em cultura apresentaram elevada taxa de proliferação apesar da diminuída expressão de fosfatase alcalina. A proliferação celular foi maior no grupo FK que CSA (p=0,0007). O PTH foi o determinante independente do fósforo sérico (p=0,042), DMO lombar (0,044) e volume osteóide (p=0,001). Conclusões: Após dois anos de transplante renal estável no qual, os principais fatores de risco para perda de massa óssea, foram afastados nenhum paciente apresentava tecido ósseo normal. Encontramos, predominantemente, diminuição da formação, aumento da reabsorção óssea e defeito de mineralização caracterizando a presença de doença mista. Esses achados se devem provavelmente à hipofosfatemia, persistência do hiperparatiroidismo, insuficiência de 25(OH) D e a ação de drogas imunossupressoras / We evaluated bone mineral metabolism and histology from twenty seven late kidney transplanted patients, as well as osteoblastic activity in vitro obtained from bone biopsies. Patients were young, with stable graft function, in use of minimal immunosuppressive drugs doses and without known risk factors for bone loss. Hypercalcemia was found in 40%, whereas 26% had hypophosphatemia, 30% hyperparathyroidism and 63% 25-OH vitamin D insuficiency. Bone volume was decreased in 30% of them with elevated bone resorption in the majority, low bone formation in 60% and mineralization defect in 46%. Osteoblastic cells on culture expressed less alkaline phosphatase despite high proliferation rate. After a high restrictive selection of the patients, they still presented mixed bone diseased. These findings are probably related to immunosuppressive drugs, persistence of hyperparathyroidism and 25-OH vitamin D insuficiency
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