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...