Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL×1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.

Fast tacrolimus metabolism is linked to inferior outcomes such as rejection and lower renal function after kidney transplantation. Renal calcineurin-inhibitor toxicity is a common adverse effect of tacrolimus therapy. The present contribution hypothesized that tacrolimus-induced nephrotoxicity is related to a low concentration/dose (C/D) ratio. We analyzed renal tubular epithelial cell cultures and 55 consecutive kidney transplant biopsy samples with tacrolimus-induced toxicity, the C/D ratio, C0, C2, and C4 Tac levels, pulse wave velocity analyses, and sublingual endothelial glycocalyx dimensions in the selected kidney transplant patients. A low C/D ratio (C/D ratio < 1.05 ng/mL×1/mg) was linked with higher C2 tacrolimus blood concentrations (19.2 ± 8.7 µg/L vs. 12.2 ± 5.2 µg/L respectively; p = 0.001) and higher degrees of nephrotoxicity despite comparable trough levels (6.3 ± 2.4 µg/L vs. 6.6 ± 2.2 µg/L respectively; p = 0.669). However, the tacrolimus metabolism rate did not affect the pulse wave velocity or glycocalyx in patients. In renal tubular epithelial cells exposed to tacrolimus according to a fast metabolism pharmacokinetic profile it led to reduced viability and increased Fn14 expression. We conclude from our data that the C/D ratio may be an appropriate tool for identifying patients at risk of developing calcineurin-inhibitor toxicity.

The Kidney Donor Profile Index (KDPI) was introduced in the United States in 2014 to guide the decision making of clinicians with respect to accepting or declining a donated kidney. To evaluate whether the KDPI can be applied to a European cohort, we retrospectively assessed 580 adult patients who underwent renal transplantation (brain-dead donors) between January 2007 and December 2014 at our center and compared their KDPIs with their short- and long-term outcomes. This led to the observation of two associations: one between the KDPI and the estimated glomerular filtration rate at one year (1-y-eGFR) and the other between the KDPI and the death-censored allograft survival rate (both p < 0.001). Following this, the individual input factors of the KDPI were analyzed to assess their potential to evaluate the quality of a donor organ. We found that a donor’s age alone is significantly predictive in terms of 1-y-eGFR and death-censored allograft survival (both p < 0.001). Therefore, a donor’s age may serve as a simple reference for future graft function. Furthermore, we found that an organ with a low KDPI or from a young donor has an improved graft survival rate whereas kidneys with a high KDPI or from an older donor yield an inferior performance, but they are still acceptable. Therefore, we would not encourage defining a distinct KDPI cut-off in the decision-making process of accepting or declining a kidney graft.

Ischemic stroke, which frequently results from middle cerebral artery occlusion (MCAO), leads to a sequence of multiphasic events, including inflammation, hemorrhagic transformation, and blood-brain barrier (BBB)-breakdown. The understanding of stroke pathology as a multistaged event consisting of primary tissue damage within the ischemic core and progressive cell damage in the surrounding penumbra gave rise to new therapeutic options in stroke treatment. 1Monocyte chemoattractant protein-1 (MCP-1) is one of the most prominent chemokines, which is expressed in neurons, astrocytes, and endothelial cells in response to oxygen shortage. 2,3 It is a dominant chemotactic factor, which attracts monocytes, neutrophil granulocytes, and macrophages into the infarcted core. 4 After experimental cerebral ischemia, mice lacking MCP-1 develop smaller infarcts, show impaired leukocyte infiltration, and an overall reduced expression of inflammatory markers interleukin (IL)-6, IL-1β, and G-CSF, which is accompanied by a less severe neurological outcome. 5,6 The BBB, a physical and metabolic barrier between blood and brain, is mainly formed by interaction of transmembrane-associated proteins claudin-5, occludin, zonula occludens (ZO)-1, and ZO-2, which connect tight-junction (TJ) proteins to the cytoskeleton. 7 In vitro studies have shown that administration of MCP-1 leads to reduced transendothelial electric resistance as well as redistribution and phosphorylation of BBB-related proteins, resulting in altered BBB-integrity. [8][9][10][11] Furthermore, it has been demonstrated that intracerebral administration of MCP-1 increases leakage of high-molecular tracer protein FITC-albumin (fluorescein isothiocyanate-albumin) into the brain, 12 thereby providing additional evidence for a crucial role of MCP-1 in poststroke BBB-breakdown. A previous study characterized TJ-protein phosphorylation via Rho/Protein Kinase C-α (PKCα) as major mechanism leading to opening of the brain endothelial barrier.9 Today, it is well accepted that alterations in morphology and expression as well as post-transcriptional and post-translational modifications of TJ-proteins Background and Purpose-Stroke-induced blood-brain barrier (BBB)-disruption can contribute to further progression of cerebral damage. There is rising evidence for a strong involvement of chemokines in postischemic BBB-breakdown. In a previous study, we showed that monocyte chemoattractant protein-1 (MCP-1)-deficiency results in a markedly reduced inflammatory reaction with decreased levels of interleukin-6, interleukin-1β, and granulocyte colony-stimulating factor after experimental stroke. With MCP-1 as one of the key players in stroke-induced inflammation, in this study, we investigated the influence of MCP-1 on poststroke BBB-disruption as well as transcription/translation of BBB-related genes/proteins after cerebral ischemia. Methods-Sixteen wild-type and 16 MCP-1 −/− mice were subjected to 30 minutes of middle cerebral artery occlusion. By injecting high molecular-tracer, we compared...

Despite screening, effective anti-viral drugs and risk-balanced prophylaxis, cytomegalovirus (CMV) remains a major cause of morbidity in transplant patients. The objective of this study was to retrospectively analyze the risk factors associated with CMV viremia after kidney transplantation in a large European cohort with standardized valganciclovir prophylaxis in the present era. A special focus was placed on the comparison of living and postmortal donation. We conducted a longitudinal observational study involving 723 adult patients with a total of 3292 patient-years who were transplanted at our center between 2007 and 2015. Valganciclovir prophylaxis was administered over 100 days for CMV+ donors (D) or recipients (R), over 200 days for D+/R−, and none in D−/R−. A CMV+ donor, rejection episodes, and deceased donor transplantation were identified to be associated with increased incidences of CMV viremia. Although we did not find a reduced overall survival rate for patients with CMV viremia, it was associated with worse graft function. Since we observed a relevant number of CMV infections despite prescribing valganciclovir prophylaxis, a pre-emptive strategy in patients with (suspected) adherence restrictions could be favored. Our data can help transplant physicians educate their patients about their individual CMV risk and choose the most appropriate CMV treatment approach.

The ‘weekend effect’ describes increased adverse outcomes after weekend hospitalization.We examined weekend-weekday differences in the outcome of 580 patients following renal transplantation (RTx, brain dead donors) between January 2007 and December 2014 at our center. 3-year patient and graft survival, incidence of delayed graft function (DGF), acute rejections and estimated glomerular filtration rate (eGFR, CKD-EPI) at 1 year as well as surgical complications were assessed. Of all 580 transplants, 416 (71.7%) were performed on weekdays (Monday-Friday) and 164 (28.3%) on weekends (Saturday-Sunday). 3-year patient and graft survival, frequencies of DGF, acute rejections and 1-year eGFR as well as length of hospital stay were similar between RTx patients transplanted on weekdays or weekends, respectively. However, a noticeable difference was detected with regard to surgical complications which were more frequent in RTx patients transplanted on weekends. All results remained consistent across all definitions of weekend status. Our results suggest that weekend transplant status does not affect functional short-term and long-term outcomes after RTx. The standardized protocols and operationalized processes applied in RTx might contribute to this finding and may provide a model for other medical procedures that are performed on weekends to improve efficiency and outcomes. The higher rate of surgical complications after weekend RTx needs further elaboration to fully assess the presence of a weekend effect in RTx.

Background Sleep deprivation is a well-known risk factor for the performance of medical professionals. Solid organ transplantation (especially orthotopic liver transplantation (oLT)) appears to be vulnerable since it combines technically challenging operative procedures with an often unpredictable start time, frequently during the night. Aim of this study was to analyze whether night time oLT has an impact on one-year graft and patient survival. Material and methods Deceased donor oLTs between 2006 and 2017 were retrospectively analyzed and stratified for recipients with a start time at day (8 a.m. and 6 p.m.) or at night (6 p.m. to 8 a.m.). We examined donor as well as recipient demographics and primary outcome measure was one-year patient and graft survival. Results 350 oLTs were conducted in the study period, 154 (44%) during daytime and 196 (56%) during nighttime. Donor and recipient variables were comparable. One-year patient survival (daytime 75.3% vs nighttime 76.5%, p = 0.85) as well as graft survival (daytime 69.5% vs nighttime 73.5%, p = 0.46) were similar between the two groups. Frequencies of reoperation (daytime 53.2% vs nighttime 55.1%, p = 0.74) were also not significantly different. Conclusion Our retrospective single center data derived from a German transplant center within the Eurotransplant region provides evidence that oLT is a safe procedure irrespective of the starting time. Our data demonstrate that compared to daytime surgery nighttime liver transplantation is not associated with a greater risk of surgical complications. In addition, one-year graft and patient survival do not display inferior results in patients undergoing nighttime transplantation.