Macrophage migration inhibitory factor in patients undergoing orthotopic liver transplantation. : Association with acute kidney injury

Die orthotope Lebertransplantation (OLT) ist die einzige kurative Therapie des terminalen Leberversagens. Nach der OLT entwickeln circa 50 % der Patienten ein akutes Nierenversagen (ANV), welches mit erhöhter Morbidität und Mortalität nach der OLT assoziiert ist. Mehrere Faktoren, wie renale Hypoperfusion, Inflammation und nephrotoxische Medikamente sind für die Entstehung des ANV verantwortlich. Da jedoch die Inzidenz des ANV nach der OLT deutlich höher ist als nach anderen chirurgischen Eingriffen, wird angenommen dass auch andere Mechanismen bei der Entstehung des ANVs nach der OLT eine Rolle spielen. Experimentelle Studien haben gezeigt dass eine ‘Fernenztündung (Remote Injury) nach der hepatalen Ischämie/Reperfusion (I/R) eine Nierendysfuntion verursachen kann. Macrophage Migration Inhibitory Factor (MIF) ist ein proinflammatorisches Zytokin, welches nach der hepatalen I/R die Produktion von Tumor Nekrose Factor , Interleukin 1, und Interleukin 6 in entfernten Geweben anregt. Somit könnte MIF eine Entzündung in den Nieren triggern und bei der Entstehung des ANVs eine Rolle spielen. Ziel dieser These war die Serumkonzentrationen von MIF in der peri-operativen Phase der OLT zu messen und zu beurteilen ob MIF mit dem ANV nach OLT assoziiert ist. Wir konnten zeigen dass die MIF Serumkonzentrationen bei Patienten während der OLT ansteigen. Unsere Ergebnisse deuten darauf hin dass die MIF Serumkonzentrationen ansteigen weil das aus der Spenderleber freigesetzte MIF nach der Reperfussion in den Empfängerkreislauf geschwemmt wird. Zusätzlich zeigten wir dass die MIF Serumkonzentrationen bei Patienten welche nach der OLT ein ANV entwickelten höher waren als bei Patienten ohne ANV. Mit Hilfe von MIF war eine frühe Diagnostik des ANVs nach OLT möglich. MIF konnte die Entstehung des ANV nach der OLT mit derselben Genauigkeit vorhersagen wie NGAL, welches als ein gut erforschter Biomarker für die Frühdiagnostik des ANVs bekannt ist. Zusammenfassend gesehen könnte MIF potentiell zukünftig im klinischen Alltag als ein Hilfsmarker für die Frühdiagnostik des ANVs eingesetzt werden.Orthotopic liver transplantation (OLT) is the only curative treatment for end-stage liver disease, which is the 14th commonest cause of death worldwide. Acute kidney injury (AKI) occurs in approximately 50% of patients undergoing orthotopic liver transplantation (OLT), and is associated with reduced graft survival as well as increased morbidity and mortality. The etiology of AKI is thought to be multifactorial, including renal hypoperfusion, inflammation, and nephrotoxic medications. Acute kidney injury occurs more frequently after OLT than after other major surgeries, suggesting the involvement of additional mechanisms responsible for the development of AKI in patients undergoing OLT. Experimental studies suggest that remote injury after hepatic ischemia/reperfusion (I/R) can induce renal dysfunction. In particular, macrophage migration inhibitory factor (MIF) - a cytokine inducing inflammatory response by upregulating production of tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6 in distant tissues after hepatic ischemia/reperfusion (I/R) - might play a role in the development of OLT-induced AKI. Hence, the aim of this thesis was to measure serum MIF concentrations in the peri-operative phase of OLT, and to assess whether MIF is associated with AKI following OLT. We demonstrate that serum MIF concentrations increase in patients undergoing OLT. Our results suggest that the human liver graft releases MIF during ischemic storage, and MIF concentrations in the recipients serum increase at least in part due to an influx of graft-released MIF. In addition, we report that serum MIF concentrations are increased in patients who develop AKI after OLT, and that MIF is a potential biomarker for early diagnosis of AKI after OLT. In patients after OLT, MIF predicted the development of AKI with similar power as NGAL, which is a well-described early marker for AKI. In conclusion, MIF is associated with AKI after OLT, and might serve as a future diagnostic tool to facilitate early detection of AKI, at least in patients after OLT.submitted by Joanna Baron-StefaniakAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Diss., 2018(VLID)295074

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Introduction Several biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT. The aim of this prospective, observational pilot study was to compare the predictive values of serum and urinary MIF for severe AKI after OLT to those of serum and urinary NGAL. Methods Concentrations of MIF and NGAL were measured in serum and urine samples collected from patients undergoing OLT. Acute kidney injury was classified according to the KDIGO criteria, with stages 2 and 3 summarized as severe AKI. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of MIF and NGAL for the development of severe AKI. Results Forty-five patients (mean age 558 years) were included. Nineteen patients (38%) developed severe AKI within 48 hours after reperfusion. At the end of OLT, serum MIF was predictive of severe AKI (AUC 0.73; 95% confidence intervals, CI 0.550.90; P = 0.03), whereas urinary MIF, serum NGAL, and urinary NGAL were not. On the first postoperative day, serum MIF (AUC 0.78; CI 0.620.93; P = 0.006), urinary MIF (AUC 0.71; CI 0.530.88; P = 0.03), and urinary NGAL (AUC 0.79; CI 0.640.93; P = 0.02) were predictive for severe AKI, while serum NGAL was not. Conclusion In the setting of OLT, MIF and NGAL had similar predictive values for the development of severe AKI.(VLID)487417

D-dopachrome tautomerase predicts outcome but not the development of acute kidney injury after orthotopic liver transplantation

© 2018 International Hepato-Pancreato-Biliary Association Inc. Background: Elevated concentrations of D-dopachrome tautomerase (D-DT) were associated with adverse outcome in various clinical settings. However, no study assessed D-DT concentrations in patients requiring orthotopic liver transplantation (OLT). The aim of this observational study was to measure serum D-DT concentrations in patients undergoing OLT and associate D-DT with survival and acute kidney injury (AKI). Methods: Forty-seven adults with end-stage liver disease undergoing OLT were included. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of D-DT for outcome and AKI after OLT. Survival was analyzed by Kaplan–Meier curves. Results: Serum D-DT concentrations were greater in non-survivors than in survivors prior to OLT (86 [50–117] vs. 53 [31–71] ng/ml, P = 0.008), and on day 1 (357 [238–724] vs. 189 [135–309] ng/ml, P = 0.001) and day 2 (210 [142–471] vs. 159 [120–204] ng/ml, P = 0.004) following OLT. Serum D-DT concentrations predicted lethal outcome when measured preoperatively (AUC = 0.75, P = 0.017) and on postoperative day 1 (AUC = 0.75, P = 0.015). One-year survival of patients with preoperative D-DT concentrations \u3e85 ng/ml was 50%, whereas that of patients with preoperative D-DT concentrations /ml was 83% (Chi2= 5.83, P = 0.016). In contrast, D-DT was not associated with AKI after OLT. Conclusion: In patients undergoing OLT, serum D-DT might predict outcome after OLT

PLOS ONE / Transfusion of standard-issue packed red blood cells induces pulmonary vasoconstriction in critically ill patients after cardiac surgeryA randomized, double-blinded, clinical trial

Background Experimental and volunteer studies have reported pulmonary vasoconstriction during transfusion of packed red blood cells (PRBCs) stored for prolonged periods. The primary aim of this study was to evaluate whether transfusion of PRBCs stored over 21 days (standard-issue, siPRBCs) increases pulmonary artery pressure (PAP) to a greater extent than transfusion of PRBCs stored for less then 14 days (fresh, fPRBCs) in critically ill patients following cardiac surgery. The key secondary aim was to assess whether the pulmonary vascular resistance index (PVRI) increases after transfusion of siPRBCs to a greater extent than after transfusion of fPRBCs. Methods The study was performed as a single-center, double-blinded, parallel-group, randomized clinical trial. Leukoreduced PRBCs were transfused while continuously measuring hemodynamic parameters. Systemic concentrations of syndecan-1 were measured to assess glycocalyx injury. After randomizing 19 patients between January 2014 and June 2016, the study was stopped due to protracted patient recruitment. Results Of 19 randomized patients, 11 patients were transfused and included in statistical analyses. Eight patients were excluded prior to transfusion, 6 patients received fPRBCs (103 storage days), whereas 5 patients received siPRBCs (334 storage days). The increase in PAP (73 vs. 22 mmHg, P = 0.012) was greater during transfusion of siPRBCs than during transfusion of fPRBCs. In addition, the change in PVRI (15089 vs. -437 dyn·s·cm·m, P = 0.018) was greater after transfusion of siPRBCs than after transfusion of fPRBCs. The increase in PAP correlated with the change of systemic syndecan-1 concentrations at the end of transfusion (R = 0.64,P = 0.034). Conclusion Although this study is underpowered and results require verification in larger clinical trials, our findings suggest that transfusion of siPRBCs increases PAP and PVRI to a greater extent than transfusion of fPRBCs in critically ill patients following cardiac surgery. Glycocalyx injury might contribute to pulmonary vasoconstriction associated with transfusion of stored blood.(VLID)495023

BMC Nephrology / Urinary [TIMP-2] [IGFBP-7] for predicting acute kidney injury in patients undergoing orthotopic liver transplantation

Background The product of the concentrations of urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 (urinary [TIMP-2][IGFBP-7]) has been suggested as biomarker for early detection of acute kidney injury (AKI) in various clinical settings. However, the performance of urinary [TIMP-2][IGFBP-7] to predict AKI has never been assessed in patients undergoing orthotopic liver transplantation (OLT). Thus, the aim of this study was to assess the early predictive value of urinary [TIMP-2][IGFBP-7] for the development of AKI after OLT. Methods In this observational study, urinary [TIMP-2][IGFBP-7] was measured in samples from adult OLT patients. AKI was diagnosed and classified according to KDIGO criteria. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of urinary [TIMP-2][IGFBP-7] for the development of AKI. Results Forty patients (mean age 558years) were included. Twenty-eight patients (70%) developed AKI stage 1, 2, or 3 within 48h after OLT. Urinary [TIMP-2][IGFBP-7] was not predictive for AKI at the end of OLT (AUC: 0.54, CI [0.320.75], P=0.72), at day 1 (AUC: 0.60, CI [0.410.79], P=0.31), or day 2 after OLT (AUC: 0.63, CI [0.460.8], P=0.18). Conclusion Based on our results, routine clinical use of urinary [TIMP-2][IGFBP-7] cannot be recommended for risk assessment of AKI in patients undergoing OLT.(VLID)489637

Area under the ROC curve for development of any stage of AKI.

<p>Area under the ROC curve for development of any stage of AKI.</p

Serum concentrations of MIF and NGAL.

<p>Concentration of (A) serum MIF and (B) serum NGAL at 4 different time points: baseline (BL; under anesthesia before skin incision), day 0 (at the end of surgery), day 1 (24 hours after graft reperfusion on day 1 after OLT), and on day 2 (48 hours after reperfusion on day 2 after OLT). White bars indicate values of patients with no AKI or stage 1 AKI, gray bars represent values of patients who developed stage 2 or 3 AKI after undergoing OLT. P values indicate significant differences between groups.</p

Demographic data of the study population.

<p>Demographic data of the study population.</p