Dokument: Die Rolle der microRNAs miR 107, miR 122 5p, miR 125b 5p und miR 192 5p als prädiktive Marker für die Erholung der Nierenfunktion nach akuter Nierenschädigung
| Titel: | Die Rolle der microRNAs miR 107, miR 122 5p, miR 125b 5p und miR 192 5p als prädiktive Marker für die Erholung der Nierenfunktion nach akuter Nierenschädigung | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=63154 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20230719-090510-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Huthmann, Laura [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. med. Brandenburger, Timo [Gutachter] Prof. Dr. Kröpil, Feride [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Die akute Nierenschädigung (acute kidney injury, AKI) wird durch einen plötzlichen Abfall der Nierenfunktion charakterisiert und betrifft etwa 50 % der Patienten auf der Intensivstation. Durch Folgen wie Elektrolytverschiebungen, Volumenüberladung und Urämie, welche den Einsatz eines Nierenersatzverfahrens notwendig machen, steigt die Morbidität und Mortalität betroffener Patienten massiv an. Zu den Hauptursachen der AKI zählen Sepsis, herzchirurgische Eingriffe und Nephrotoxine. Die Therapie beschränkt sich auf den Einsatz eines Nierenersatzverfahrens (renal replacement therapy, RRT), wobei ursächliche Behandlungsmöglichkeiten fehlen. Biomarker, welche die Erholung der Nierenfunktion anzeigen, könnten nicht nur helfen, bekannte Methoden zur Nephroprotektion zielgerichteter auszuschöpfen oder eine RRT frühzeitig zu beginnen. Sie hätten auch das Potential, die Therapiemöglichkeiten zu erweitern. Bisher existiert jedoch weder eine Konsensusdefinition der Erholung nach AKI, noch wurden entsprechende Biomarker validiert. In diesem Kontext traten in den letzten Jahren nicht-kodierende RNAs (noncoding-RNAs, ncRNAs) immer weiter in den Fokus der Forschung. Eine gut untersuchte Gruppe sind die nur 20 bis 22 Nukleotide langen microRNAs (miRNAs). Durch Beeinflussung der Genexpression besitzen sie in physiologischen und pathophysiologischen Abläufen eine Schlüsselfunktion und könnten nicht nur als Marker für eine Nierenschädigung, sondern auch als prognostische Marker für eine Erholung der Nierenfunktion und möglicherweise sogar als therapeutische Angriffspunkte dienen.
In dieser Pilotstudie wurde untersucht, ob miRNAs als prognostische Marker für die Erholung der Nierenfunktion nach AKI geeignet sind. Nach Genehmigung durch die Ethikkommission Düsseldorf wurden 71 Patienten auf der Intensivstation, die eine höhergradige AKI (Stadium 2 oder 3 nach KDIGO) entwickelten, eingeschlossen. Zu vier Zeitpunkten wurden Plasma- und Urinproben entnommen. Anhand des Verlaufs des Serum-Kreatinins teilten wir die Patienten in zwei Gruppen ein: 1) Erholung der Nierenfunktion oder 2) persistierende AKI. Kriterium für die Erholung war ein Rückgang des Serumkreatinins ohne RRT auf das 1,5 fache des Ausgangs-Kreatinins innerhalb von sieben Tagen. Im Laufe des Krankenhausaufenthaltes und für die Dauer eines Jahres wurden klinische Daten erfasst. Plasmaproben von Tag 1 von sechs repräsentativ ausgewählten Patienten mit und ohne Erholung der Nierenfunktion wurden mittels NextGenerationSequencing (NGS) auf differentielle miRNA-Expression untersucht und vielversprechende miRNAs ausgewählt. Zusammenhänge mit AKI-assoziierten Proteinnetzwerken wurden durch Netzwerkanalysen identifiziert. Durch quantitative Echtzeit-Polymerasekettenreaktion wurden die Expressionsunterschiede an Tag 1 und Tag 7 zwischen den Patientengruppen verifiziert. Von den eingeschlossenen Patienten (n = 71) erholten sich 18, bei 53 persistierte die AKI. Im NGS und der anschließenden Netzwerkanalyse identifizierten wir mehrere differentiell exprimierte miRNAs. Auch die qPCR bestätigte signifikante Expressionsunterschiede an Tag 1. MiR 107, miR 122 5p, miR 125b 5p und miR 192 5p waren an Tag 1 in der Gruppe mit persistierender AKI deutlich stärker exprimiert als in der Gruppe mit Erholung der Nierenfunktion. MiRNAs sind vielversprechende frühe prognostische Marker für die Erholung nach Nierenschädigung. Bei vier miRNAs konnten wir den Zusammenhang zwischen erhöhter Expression und persistierender AKI verifizieren. Unsere Ergebnisse könnten dazu beitragen, die Prognose von AKI-Patienten frühzeitig abzuschätzen und dadurch helfen, die Behandlung entsprechend anzupassen. Multizentrische Studien mit einem größeren Patientenklientel müssen folgen, um die Ergebnisse zu verifizieren.Acute kidney injury (AKI) affects about 50 % of patients in intensive care. The main causes are infection and sepsis, cardiac surgery, and the use of nephrotoxins. AKI entails electrolyte disturbances, volume overload, and uremia, which then cause the need for renal replacement therapy (RRT) and increase morbidity and mortality. To date, there are no validated parameters to describe recovery from AKI. Non-coding RNAs (ncRNAs) and especially microRNAs (miRNAs), one subtype that is only 20 to 22 nucleotides long, have come into focus of research. MiRNAs affect genetic expression and therefore play a crucial role in physiological and pathological processes. Hence they might be suitable not only as markers of AKI but also in prognostic assessment and even as therapeutic targets. This trial focused on the investigation of whether miRNAs can be used as prognostic markers for recovery after AKI. After approval of the Düsseldorf Ethics committee (Study number 6138R), patients in intensive care that developed AKI stage 2 or 3 (KDIGO-criteria) were included. Blood and urine samples were collected at four time points. Depending on the course of serum-creatinine patients were divided into two groups: 1) patients who recovered from AKI or 2) patients with persistent AKI. The criterion for recovery was a decline in serum-creatinine without RRT below the 1.5-fold of baseline creatinine within seven days. During the hospital stay and for the following year, clinical data was collected. Using NextGenerationSequencing (NGS) plasma samples of six representative patients, collected on day 1, were analyzed for differences in miRNA expression. Network analyses revealed interactions with protein networks that are known to affect AKI. After selecting promising miRNAs, quantitative Real-Time PCR (qPCR) was used to quantify differences in expression between the groups on days 1 and 7. 71 patients were included, 18 recovered within seven days, 53 had persistent AKI. NGS and network analyses identified various differentially expressed miRNAs and qPCR confirmed that these differences were significant on day 1. This could not be shown on day 7. MiR 107, miR 122 5p, miR 125b 5p, and miR 192 5p were significantly higher expressed on day 1 in patients with persistent AKI. MiRNAs are promising early prognostic biomarkers for recovery after AKI. This study showed that overexpression of the four studied miRNAs was associated with persistent AKI. These results could help assess the prognosis of patients with AKI early and help guide treatment. Multicenter studies including more patients will be needed to verify our findings. | |||||||
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| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 19.07.2023 | |||||||
| Dateien geändert am: | 19.07.2023 | |||||||
| Promotionsantrag am: | 24.12.2022 | |||||||
| Datum der Promotion: | 11.07.2023 |
