The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection

Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. We used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. We identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)–incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, we showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation

Determinants of patient and graft survival in the elderly recipients of a kidney graft

Elderly patients represent an increasing proportion of kidney transplant recipients. Yet factors that determine their post-transplantation outcomes remain poorly defined.The aim of this study was to identify pre- and post-transplant predictors of patient and graft survival in elderly recipients of kidney grafts.We performed a population-based retrospective cohort study involving patients aged 60 years or older who received a first cadaveric kidney transplant. Potential outcome predictors were identified with survival analyses based on a Cox proportional hazard model.Active smoking at transplantation, increased body mass index and time on dialysis before transplantation were significantly associated with an increased risk of post-transplant mortality and graft loss. Decreased graft function at one year was associated with a higher risk of mortality and graft loss beyond one year post-transplant.In conclusion, our study has identified potential targets for interventions aimed at improving patient and graft survival in elderly patients

Acute Kidney Injury: Preclinical Innovations, Challenges, and Opportunities for Translation

Background: Acute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice. Objective: This article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice. Sources of Information: MEDLINE, ISI Web of Science Findings: This paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition. Limitations: This review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature. Implications: Translation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations

Acute kidney injury: preclinical innovations, challenges, and opportunities for translation

Abstract Background Acute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice. Objective This article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice. Sources of Information MEDLINE, ISI Web of Science Findings This paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition. Limitations This review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature. Implications Translation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations

Predicting Time to and Average Quality of Future Offers for Kidney Transplant Candidates Declining a Current Deceased Donor Kidney Offer: A Retrospective Cohort Study

Background: At the time a kidney offer is made by an organ donation organization (ODO), transplant physicians must inform candidates on the pros and cons of accepting or declining the offer. Although physicians have a general idea of expected wait time to kidney transplantation by blood group in their ODO, there are no tools that provide quantitative estimates based on the allocation score used and donor/candidate characteristics. This limits the shared decision-making process at the time of kidney offer as (1) the consequences of declining an offer in terms of wait-time prolongation cannot be provided and (2) the quality of the current offer cannot be compared with that of offers that could be made to the specific candidate in the future. This is especially relevant to older transplant candidates as many ODOs use some form of utility matching in their allocation score. Objective: We aimed to develop a novel method to provide personalized estimates of wait time to next offer and quality of future offers for kidney transplant candidates if they refused a current deceased donor offer from an ODO. Design: A retrospective cohort study. Setting: Administrative data from Transplant Quebec. Patients: All patients who were actively registered on the kidney transplant wait list at any point between March 29, 2012 and December 13, 2017. Measurements: The time to next offer was defined as the number of days between the time of the current offer and the next offer if the current one were declined. The quality of the offers was measured with the 10-variable Kidney Donor Risk Index (KDRI) equation. Methods: Candidate-specific kidney offer arrival was modeled with a marked Poisson process. To derive the lambda parameter for the marked Poisson process for each candidate, the arrival of donors was examined in the 2 years prior to the time of the current offer. The Transplant Quebec allocation score was calculated for each ABO-compatible offer with the characteristics that the candidate presented at the time of the current offer. Offers where the candidate’s score was lower than the scores of actual recipients of the second kidneys transplanted were filtered out from the candidate-specific kidney offer arrival. The KDRIs of offers that remained were averaged to provide an estimate of the quality of future offers, to be compared with that of the current offer. Results: During the study period, there were 848 unique donors and 1696 transplant candidates actively registered. The models provide the following information: average time to next offer, time to which there is a 95% probability of receiving a next offer, average KDRI of future offers. The C-index of the model was 0.72. When compared with providing average group estimates of wait time and KDRI of future offers, the model reduced the root-mean-square error in the predicted time to next offer from 137 to 84 days and that of predicted KDRI of future offers from 0.64 to 0.55. The precision of the model’s predictions was higher when observed times to next offer were 5 months or less. Limitations: The models assume that patients declining an offer remain wait-listed until the next one. The model only updates wait time every year after the time of an offer and not in a continuous fashion. Conclusion: By providing personalized quantitative estimates of time to and quality of future offers, our new approach can inform the shared decision-making process between transplant candidates and physicians when a kidney offer from a deceased donor is made by an ODO

Therapeutic Management in Patients with Renal Failure who Experience an Acute Coronary Syndrome

Background and objectives: Prior reports have suggested that patients with impaired renal function receive less aggressive care after an acute coronary syndrome (ACS). The aim of this study was to determine whether this held true in a contemporary cohort, after thorough adjustment for cotreatments/comorbidities