TY  - THES
A1  - Devine, Eric
T1  - Increased removal of protein bound uremic toxins through reversible modification of the ionic strength during hemodiafiltration
T1  - Erhöhte Elimination proteingebundener Urämietoxine durch reversible Modifikation der Ionenstärke während der Hämodiafiltration
N2  - A large number of metabolic waste products accumulate in the blood of patients with renal failure. Since these solutes have deleterious effects on the biological functions, they are called uremic toxins and have been classified in three groups: 1) small water soluble solutes (MW < 500 Da), 2) small solutes with known protein binding (MW < 500 Da), and 3) middle molecules (500 Da < MW < 60 kDa). Protein bound uremic toxins are poorly removed by conventional hemodialysis treatments because of their high protein binding and high distribution volume. The prototypical protein bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are associated with the progression of chronic kidney disease, cardiovascular outcomes, and mortality of patients on maintenance hemodialysis. Furthermore, these two compounds are bound to albumin, the main plasma protein, via electrostatic and/or Van-der-Waals forces. The aim of the present thesis was to develop a dialysis strategy, based on the reversible modification of the ionic strength in the blood stream by increasing the sodium chloride (NaCl) concentration, in order to enhance the removal of protein bound substances, such as IS and pCS, with the ultimate goal to improve clinical patient outcomes. Enhancing the NaCl concentration ([NaCl]) in both human normal and uremic plasma was efficient to reduce the protein bound fraction of both IS and pCS by reducing their binding affinity to albumin. Increasing the ionic strength was feasible during modified pre-dilution hemodiafiltration (HDF) by increasing the [NaCl] in the substitution fluid. The NaCl excess was adequately removed within the hemodialyzer. This method was effective to increase the removal rate of both protein bound uremic toxins. Its ex vivo hemocompatibility, however, was limited by the osmotic shock induced by the high [NaCl] in the substituate. Therefore, modified pre-dilution HDF was further iterated by introducing a second serial cartridge, named the serial dialyzers (SDial) setup. This setting was validated for feasibility, hemocompatibility, and toxin removal efficiency. A better hemocompatibility at similar efficacy was obtained with the SDial setup compared with the modified pre-dilution HDF. Both methods were finally tested in an animal sheep model of dialysis to verify biocompatibility. Low hemolysis and no activation of both the complement and the coagulation systems were observed when increasing the [NaCl] in blood up to 0.45 and 0.60 M with the modified pre-dilution HDF and the SDial setup, respectively. In conclusion, the two dialysis methods developed to transitory enhance the ionic strength in blood demonstrated adequate biocompatibility and improved the removal of protein bound uremic toxins by decreasing their protein bound fraction. The concepts require follow-on clinical trials to assess their in vivo efficacy and their impact on long-term clinical outcomes.
N2  - Eine große Zahl von Stoffwechselprodukten akkumuliert im Blut urämischer Patienten mit Nierenversagen. Da diese Moleküle schädliche Wirkungen auf die biologischen Funktionen haben, werden sie als Urämietoxine bezeichnet. Man teilt sie in drei Gruppen ein: 1) kleine wasserlösliche Substanzen (MG < 500 Da), 2) kleine, proteingebundene Substanzen (MG < 500 Da), 3) Mittelmoleküle (500 Da < MG < 60 kDa). Proteingebundene Urämietoxine werden wegen ihrer starken Proteinbindung und ihres Verteilungsvolumen durch klassische Hämodialyseverfahrens nur schlecht entfernt. Die prototypischen proteingebundenen Urämietoxine Indoxylsulfat (IS) und p-Cresylsulfat (pCS) sind bei chronischen niereninsuffizienten Patienten mit dem Fortschreiten der Niereninsuffizienz, Herz-Kreislauf-Erkrankungen und der Mortalität verbunden. Außerdem sind diese beiden Toxine an Albumin, dem wichtigsten Plasmaprotein, durch elektrostatische und/oder Van-der-Waals-Kräfte gebunden. Das Ziel der vorliegenden Arbeit war es, ein Dialyseverfahren basierend auf einer reversiblen Modifikation der Ionenstärke im Blut durch Erhöhung der Natriumchlorid (NaCl)-Konzentration zu entwickeln, um die Entfernung von proteingebundenen Molekülen wie IS und pCS zu erhöhen und dadurch eine Verbesserung des klinischen Verlauf der Patienten zu erreichen. Die Erhöhung der NaCl-Konzentration ([NaCl]) sowohl in normalem als auch in urämischem menschlichem Plasma war geeignet, um den proteingebundenen Anteil von IS und pCS durch Schwächung ihrer Bindungsaffinität zu Albumin zu verringern. Die Erhöhung der Ionenstärke während einer modifizierten Prädilutions-Hämodiafiltration (HDF) konnte durch eine Erhöhung der [NaCl] in der Substitutionslösung umgesetzt werden; dabei wurde der NaCl-Überschuss innerhalb des Dialysators vollständig entfernt. Dieses Verfahren war effektiv, um die Entfernungsrate beider proteingebundenen Urämietoxine zu steigern; seine Ex-vivo-Hämokompatibilität war allerdings aufgrund des osmotischen Schocks infolge der hohen [NaCl] im Substituat begrenzt. Deshalb wurde eine Iteration der modifizierten Prädilutions-HDF durch Einbau eines zweiten, seriellen Dialysators vorgenommen, bezeichnet als serielles Dialysator System (SDial). Diese letzte Methode wurde dann bezüglich der Durchführbarkeit, der Hämokompatibilität und Toxinentfernung validiert. Durch das SDial-System konnte, verglichen mit der modifizierten Prädilutions-HDF, eine bessere Hämokompatibilität bei ähnlicher Wirksamkeit erzielt werden. Beide Methoden, modifizierte Prädilutions-HDF und SDial System, wurden abschließend in ein Tierdialysemodell mit Schafen transferiert, wobei eine zufriedenstellende Biokompatibilität demonstriert werden konnte. Beide, zur vorübergehenden Erhöhung der Ionenstärke im Blut entwickelten Dialyseverfahren zeigten bei zufriedenstellender Biokompatibilität eine verbesserte Entfernung proteingebundener Urämietoxine durch Reduktion ihrer proteingebundenen Fraktion. In einem nächsten Schritt sind klinische Studien erforderlich, die diese Konzepte bezüglich ihrer In-vivo-Wirksamkeit und ihrer langfristigen Wirkung auf den Krankheitsverlauf untersuchen.
KW  - Hämodiafiltration
KW  - Ionenstärke
KW  - Proteinbindung
KW  - Urämietoxine
KW  - Hämodialyse
KW  - Biokompatibilität
KW  - Ionic strength
KW  - protein binding
KW  - uremic toxin
KW  - hemodialysis
KW  - biocompatibility
KW  - Urämie
KW  - Toxin
KW  - Ionenstärke
KW  - Blut
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-83583
ER  - 
TY  - JOUR
A1  - Klement, Rainer Johannes
A1  - Frobel, Thomas
A1  - Albers, Torsten
A1  - Fikenzer, Sven
A1  - Prinzhausen, Jan
A1  - Kämmerer, Ulrike
T1  - A pilot case study on the impact of a self-prescribed ketogenic diet on biochemical parameters and running performance in healthy and physically active individuals
N2  - Background: Ketogenic diets (KDs) have gained some popularity not only as effective weight-loss diets and treatment options for several diseases, but also among healthy and physically active individuals for various reasons. However, data on the effects of ketosis in the latter group of individuals are scarce. We therefore collected pilot data on the physiological response to a self-prescribed ketogenic diet lasting 5-7 weeks in a small cohort of healthy and physically active individuals. Methods: Twelve subjects (7 males, 5 females, age 24-60 years) who followed moderate to intensive exercise routines underwent blood testing, bioelectrical impedance analysis (BIA) and spiroergometry during an incremental treadmill test. On the next day, they went on a self-prescribed KD for a median of 38 days (range 35-50 days), after which the same tests were performed again. Ketosis was self-monitored by urinary ketone strips. Subjective feeling during the diet was assessed by a questionnaire after the intervention. Due to the small and heterogenous sample, the results are interpreted in the context of the already existing literature. Results: The KDs were tolerated well by the majority of individuals. Impaired recovery from exercise remained the most frequently reported side effect until the end of the study. Most blood parameters remained stable during the intervention. However, there were significant elevations of total and LDL cholesterol concentrations (p<0.01) and a trend towards increased HDL-cholesterol (p=0.05). The drastic reduction of carbohydrates had no statistically significant influence on running performance judged by the time to exhaustion, VO2max and respiratory compensation points. BIA measurements showed significant increases in phase angle (p=0.01) indicating improvements of body composition with an estimated decrease of 3.4 kg of fat mass (p=0.002) and gain of 1.3 kg of fat free mass. We discuss the validity of these estimates taking into account a possibly altered hydration status due to the KD. Conclusions: Active healthy individuals will probably experience no major problems during a short term KD lasting several weeks. The drastically reduced carbohydrate content of the diet seems to be no limiting factor for running performance. In addition, improvements in body composition can be expected. While most biochemical parameters are not influenced by the diet, there seems to be an impact on the blood lipid profile that could be considered problematic with respect to cardiovascular disease risk. However, the predictive role of cholesterol levels alone in individuals undergoing regular physical activity remains to be elucidated.
KW  - Fettgehalt
KW  - Blut
KW  - Ketogene Kost
KW  - High fat diet
KW  - exercise
KW  - bioimpedance analysis
KW  - blood lipids; fat loss; running performance
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78901
ER  -