Role of donor macrophages after heart and lung transplantation

Since the 1960s, heart and lung transplantation has remained the optimal therapy for patients with end‐stage disease, extending and improving quality of life for thousands of individuals annually. Expanding donor organ availability and immunologic compatibility is a priority to help meet the clinical demand for organ transplant. While effective, current immunosuppression is imperfect as it lacks specificity and imposes unintended adverse effects such as opportunistic infections and malignancy that limit the health and longevity of transplant recipients. In this review, we focus on donor macrophages as a new target to achieve allograft tolerance. Donor organ‐directed therapies have the potential to improve allograft survival while minimizing patient harm related to global suppression of recipient immune responses. Topics highlighted include the role of ontogenically distinct donor macrophage populations in ischemia–reperfusion injury and rejection, including their interaction with allograft‐infiltrating recipient immune cells and potential therapeutic approaches. Ultimately, a better understanding of how donor intrinsic immunity influences allograft acceptance and survival will provide new opportunities to improve the outcomes of transplant recipients.     

Coronary computed tomography–angiography quantitative plaque analysis improves detection of early cardiac allograft vasculopathy: A pilot study

Cardiac allograft vasculopathy (CAV) is an increasingly important complication after cardiac transplant. We assessed the additive diagnostic benefit of quantitative plaque analysis in patients undergoing coronary computed tomography–angiography (CCTA). Consecutive patients undergoing CCTA for CAV surveillance were identified. Scans were visually interpreted for coronary stenosis. Semiautomated software was used to quantify noncalcified plaque (NCP), as well as its components. Optimal diagnostic cut‐offs for CAV, with coronary angiography as gold standard, were defined using receiver operating characteristic curves. In total, 36 scans were identified in 17 patients. CAV was present in 17 (46.0%) reference coronary angiograms, at a median of 1.9 years before CCTA. Median NCP (147 vs 58, P < .001), low‐density NCP (median 4.5 vs 0.9, P = .003), fibrous plaque (median 76.1 vs 31.1, P = .003), and fibrofatty plaque (median 63.6 vs 27.6, P < .001) volumes were higher in patients with CAV, whereas calcified plaque was not (median 0.0 vs 0.0, P = .510). Visual assessment of CCTA alone was 70.6% sensitive and 100% specific for CAV. The addition of total NCP volume increased sensitivity to 82.4% while maintaining 100% specificity. NCP volume is significantly higher in patients with CAV. The addition of quantitative analysis to visual interpretation improves the sensitivity for detecting CAV without reducing specificity.     

Molecular diagnosis of kidney transplant failure based on urine

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.     

Does alcohol increase the risk of overdose death: the need for a translational approach

Background We argue for a translational approach to addiction science, using an important current research question as a case study. Case study What is the evidence in support of the hypothesis that alcohol increases the risk of a heroin/opiate overdose through a pharmacological interaction? Findings The positive epidemiological evidence shows that opiate overdose deaths rarely involve a single drug; that alcohol is the most common other drug involved; that there is a negative association between alcohol and morphine concentration at post mortem; and that post‐mortem levels of morphine are often below the levels expected of highly tolerant individuals. The evidence is consistent with the hypothesis that heroin users who drink may require less heroin to overdose than those who do not drink (all other factors being equal) because of a pharmacological interaction. However, the evidence is consistent with, and does not rule out, other causal (and non‐causal) pathways. Alcohol could be associated negatively with tolerance, or confounded by other factors. Experimental evidence is required which is unlikely to be obtained through further epidemiological study or through randomized clinical trials. Conclusions We believe that animal models could provide the key evidence to test the hypothesis for a ‘pharmacodynamic’ or ‘pharmacokinetic’ interaction, which could be corroborated in clinical challenge studies and epidemiological studies. Such a translational approach demands greater collaboration between addiction scientists from basic to applied science and from neuroscience to social science, and would be able to address other key research questions and hypotheses in addiction.