Visualizing TGF-ß and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation

Transplant surger

Histological evaluation disqualifies IMT and calcification scores as surrogates for grading coronary and aortic atherosclerosis

__Background/objectives__ Carotid intimal media thickness (IMT) and coronary calcium scores (CCS) are thought to reflect atherosclerotic burden. The validity of this assumption for IMT is challenged by recent meta-analyses; for CCS by absence of a relationship between negative scores, and freedom of future events. As such, we considered evaluation of the relationship between tissue IMT and CCS, and extend of atherosclerotic disease relevant. __Methods__ Analyses were performed on donor aortas obtained during renal graft procurement, and on coronary arteries collected during heart valve procurement for tissue donation. Movat pentachrome and Hematoxylin staining was performed, and the degree of atherosclerosis histologically graded. IMT and presence of calcium deposits were quantified on graded tissue sections. __Results__ 304 aortas and 185 coronary arteries covering the full atherosclerotic spectrum were evaluated. Aortas and coronaries showed similar relationships between tissue IMT and degree of atherosclerosis, with gradual increase in tissue IMT during earlier phases of atherosclerosis (r = 0.68 and r = 0.30, P < 0.00001 for aorta and coronaries respectively), followed by plateauing of the curve in intermediate and advanced stages. Results for tissue IMT reveal high variability, resulting in wide confidence intervals. Results for CCS are similar for aorta and coronaries, with calcium depositions limited to advanced lesions. __Conclusions__ Histological IMT measurements for the aorta and coronaries show large variations around the trend and plateauing of, and possibly reductions in IMT in late stage atherosclerotic disease. These observations for the aorta and coronaries may (partly) explain the limited benefit of including carotid IMT in risk prediction algorithms

Improving outcomes for donation after circulatory death kidney transplantation: Science of the times

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects.Transplant surger

Donor diabetes mellitus is a risk factor for diminished outcome after liver transplantation:a nationwide retrospective cohort study

BACKGROUND: With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes. METHODS: From a national cohort of adult liver transplant recipients (1996-2016), all recipients transplanted with a liver from a DM donor (n=69) were matched 1:2 with recipients of livers from non-DM donors (n=138). The primary end-point included early post-transplant outcome, such as the incidence of primary non-function (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analysis was used to analyze the impact of donor DM on graft failure. RESULTS: PNF was observed in 5.8% of grafts from DM donors versus 2.9% of non-DM donor grafts (p=0.31). Recipients of grafts derived from DM donors had a higher incidence of HAT (8.7% vs. 2.2%, p=0.03) and decreased 90-day graft survival (88.4% [70.9-91.1] vs. 96.4% [89.6-97.8], p=0.03) compared to recipients of grafts from non-DM donors. The adjusted hazard ratio for donor DM on graft survival was 2.21 (1.08-4.53, p=0.03). CONCLUSION: Donor DM is associated with diminished outcome early after liver transplantation. The increased incidence of HAT after transplantation of livers from DM donors requires further research

Circumventing the crabtree effect in cell culture: a systematic review

Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile technique for the elaboration of physiology and disease, studying metabolism using standard cell culture protocols is profoundly interfered by the Crabtree effect. This phenomenon refers to the adaptation of cultured cells to a glycolytic phenotype, away from aoxidative phosphorylation in glucose-containing medium, and questions the applicability of cell culture in certain fields of research. In this systematic review we aim to provide a comprehensive overview and critical appraisal of strategies reported to circumvent the Crabtree effect.Toxicolog

Pancreas Transplantation With Grafts From Donors Deceased After Circulatory Death: 5 Years Single-Center Experience

Transplant surger

Qualitative evaluation of coronary atherosclerosis in a large cohort of young and middle-aged Dutch tissue donors implies that coronary thrombo-embolic manifestations are stochastic

Vascular Surger

A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss

Early graft loss (EGL) is a feared outcome of kidney transplantation. Consequently, kidneys with an anticipated risk of EGL are declined for transplantation. In the most favorable scenario, with optimal use of available donor kidneys, the donor pool size is balanced by the risk of EGL, with a tradeoff dictated by the consequences of EGL. To gauge the consequence of EGL we systematically evaluated its impact in an observational study that included all 10,307 deceased-donor kidney transplantations performed in The Netherlands between 1990 and 2018. Incidence of EGL, defined as graft loss within 90 days, in primary transplantation was 8.2% (699/8,511). The main causes were graft rejection (30%), primary nonfunction (25%), and thrombosis or infarction (20%). EGL profoundly impacted short- and long-term patient survival (adjusted hazard ratio; 95% confidence interval: 8.2; 5.1-13.2 and 1.7; 1.3-2.1, respectively). Of the EGL recipients who survived 90 days after transplantation (617/699) only 440 of the 617 were relisted for re-transplantation. Of those relisted, only 298 were ultimately re-transplanted leading to an actual re-transplantation rate of 43%. Noticeably, re-transplantation was associated with a doubled incidence of EGL, but similar long-term graft survival (adjusted hazard ratio 1.1; 0.6-1.8). Thus, EGL after kidney transplantation is a medical catastrophe with high mortality rates, low relisting rates, and increased risk of recurrent EGL following re-transplantation. This implies that detrimental outcomes also involve convergence of risk factors in recipients with EGL. The 8.2% incidence of EGL minimally impacted population mortality, indicating this incidence is acceptable

Improving outcomes for donation after circulatory death kidney transplantation:Science of the times

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects

Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures

Transplant surger