Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy : a prospective cohort study

Background: In intensive care unit (ICU) patients, acute kidney injury treated with renal replacement therapy (AKI-RRT) is associated with adverse outcomes. The aim of this study was to evaluate variables associated with long-term survival and kidney outcome and to assess the composite endpoint major adverse kidney events (MAKE; defined as death, incomplete kidney recovery, or development of end-stage renal disease treated with RRT) in a cohort of ICU patients with AKI-RRT. Methods: We conducted a single-center, prospective observational study in a 50-bed ICU tertiary care hospital. During the study period from August 2004 through December 2012, all consecutive adult patients with AKI-RRT were included. Data were prospectively recorded during the patients' hospital stay and were retrieved from the hospital databases. Data on long-term follow-up were gathered during follow-up consultation or, in the absence of this, by consulting the general physician. Results: AKI-RRT was reported in 1292 of 23,665 first ICU admissions (5.5 %). Mortality increased from 59.7 % at hospital discharge to 72.1 % at 3 years. A Cox proportional hazards model demonstrated an association of increasing age, severity of illness, and continuous RRT with long-term mortality. Among hospital survivors with reference creatinine measurements, 1-year renal recovery was complete in 48.4 % and incomplete in 32.6 %. Dialysis dependence was reported in 19.0 % and was associated with age, diabetes, chronic kidney disease (CKD), and oliguria at the time of initiation of RRT. MAKE increased from 83.1 % at hospital discharge to 93. 7 % at 3 years. Multivariate regression analysis showed no association of classical determinants of outcome (preexisting CKD, timing of initiation of RRT, and RRT modality) with MAKE at 1 year. Conclusions: Our study demonstrates poor long-term survival after AKI-RRT that was determined mainly by severity of illness and RRT modality at initiation of RRT. Renal recovery is limited, especially in patients with acute-on-chronic kidney disease, making nephrological follow-up imperative. MAKE is associated mainly with variables determining mortality

VEGF receptor-2 (flk-1) overexpression in mice counteracts focal epileptic seizures.

Vascular endothelial growth factor (VEGF) was first described as an angiogenic agent, but has recently also been shown to exert various neurotrophic and neuroprotective effects in the nervous system. These effects of VEGF are mainly mediated by its receptor, VEGFR-2, which is also referred to as the fetal liver kinase receptor 1 (Flk-1). VEGF is up-regulated in neurons and glial cells after epileptic seizures and counteracts seizure-induced neurodegeneration. In vitro, VEGF administration suppresses ictal and interictal epileptiform activity caused by AP4 and 0 Mg(2+) via Flk-1 receptor. We therefore explored whether increased VEGF signaling through Flk-1 overexpression may regulate epileptogenesis and ictogenesis in vivo. To this extent, we used transgenic mice overexpressing Flk-1 postnatally in neurons. Intriguingly, Flk-1 overexpressing mice were characterized by an elevated threshold for seizure induction and a decreased duration of focal afterdischarges, indicating anti-ictal action. On the other hand, the kindling progression in these mice was similar to wild-type controls. No significant effects on blood vessels or glia cells, as assessed by Glut1 and GFAP immunohistochemistry, were detected. These results suggest that increased VEGF signaling via overexpression of Flk-1 receptors may directly affect seizure activity even without altering angiogenesis. Thus, Flk-1 could be considered as a novel target for developing future gene therapy strategies against ictal epileptic activity

VEGF protects motor neurons against excitotoxicity by upregulation of GluR2

Influx of Ca(2+) ions through the alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors is toxic to neurons and contributes to motor neuron degeneration observed in amyotrophic lateral sclerosis (ALS). The Ca(2+) permeability of the AMPA receptor depends on its subunit composition. If the GluR2 subunit is present in the receptor complex, the AMPA receptor is impermeable to Ca(2+). In this study, we identified vascular endothelial growth factor-A (VEGF) as a GluR2 inducing molecule. Cultured motor neurons pretreated with VEGF displayed higher GluR2 levels. This resulted in AMPA receptor currents with a low relative Ca(2+) permeability and in motor neurons that were less vulnerable to AMPA receptor-mediated excitotoxicity. This effect of VEGF was mediated through the VEGFR2 present on the motor neurons and was due to stimulation of GluR2 transcription. Intracerebroventricular treatment with VEGF similarly induced GluR2 expression in the ventral spinal cord of rats and this mechanism contributes to the protective effect of VEGF on motor neurons.status: publishe

Flk-1 OE mice have higher threshold for seizure-induction and exhibit shorter afterdischarge durations of seizures.

<p>(A) Mean afterdischarge (AD) threshold during focal epileptiform activity of at least 5 sec duration measured one week after electrode implantation of WT and Flk-1 OE mice. (B) AD duration for different seizure stages during kindling stimulations. Values are presented as mean ±SEM, ** <i>p</i><0.01 and *** <i>p</i><0.001.</p

Glucose transporter 1 (Glut1) immunohistochemistry and quantification of blood vessels in the hippocampal slices.

<p>(A) Intensity and distribution of Glut-1 immunostaining is similar in the hippocampus of Flk-1 OE mice compared to (B) controls; Quantification of blood vessel area (C), as well as the blood vessel density (D) showed no significant differences (<i>p</i>>0.05) between the groups. The number of glial fibrillary acidic protein (GFAP)-positive cells in wild-type mice (E) and Flk-1 OE mice (F) in the hilus of the dentate gyrus after kindling are unaltered (G). Values are presented as mean ±SEM. Scale bar is set to 30 µm.</p

Epileptogenesis is not alternated by overexpression of Flk-1.

<p>(A) Progression of kindling: mean stage during each kindling stimulation analyzed with one-way ANOVA. (B) Number of stimulations needed to reach different behavioral seizure stages. (C) Placement of electrodes for electrical stimulation in the hippocampus was verified by cresyl violet staining at the end of the experiments. Solid black dots for WT mice and black rings for Flk-1 OE mice.</p

Real-time-PCR shows high levels of Flk-1 and VEGF in the hippocampus of Flk-1 OE mice.

<p>(A) Flk-1 expression was 5.58 fold higher in Flk-1 OE mice. (B) VEGF levels in the hippocampus of animals with Flk-1 OE were 1.44 fold higher than WT mice. The cDNA was normalized to β-actin expression levels. Values are presented as mean ± SEM, ** <i>p</i><0.01 and *** <i>p</i><0.001.</p