Pavlenko, D. (2018)
Towards improved removal of uremic toxins from human plasma
Enschede DOI: 10.3990/1.9789036544788
Denys Pavlenko was a PhD Student in the research group Biomaterials Science and Technology. His supervisor was Professor Dimitrios Stamatialis from the Faculty of Science and Technology.
Hemodialysis is well-established clinical solution to sustain the life of kidney patients while they wait for transplantation. Despite impressive development in the field of hemodialysis, mortality rate remains high mostly due to inadequate removal of uremic toxins. Therefore, this thesis is focused on the developments in uremic toxin removal which will provide kidney patients with more efficient and complete treatment.
Chapter 1 provides overview of the state-of-art of blood purification techniques as well as highlights bottlenecks of current technologies. It also discusses the use of mixed matrix membranes (MMM), that combine benefits of two widely used techniques: hemodialysis and hemoperfusion. This chapter finally formulates aim and presents the general structure of the thesis.
Chapter 2 discusses development and performance of a new MMM. Firstly, essential steps to bring the MMM from a concept to a tool that provides better removal of protein-bound toxins from human plasma are reported. Secondly, the MMM performance in uremic toxin removal from human plasma is studied and compared to industrial membranes. The optimized MMM offer superior ability in removing the PBUT indoxyl sulfate (IS) and p-cresyl sulfate (pCS) in comparison to first generation MMMs (30% and 125% respectively), as well as, a commercial dialysis membrane (more than 100% better removal). The obtained results of the optimized MMM, as well as their comparison to literature studies, indicate the high potential of MMM for clinical implementation.
Chapter 3 provides insights into the blood compatibility of newly developed MMM and compares them to benchmark hemodialysis membranes. The absence of any negative response of the patient blood is an important aspect of all new medical membranes and medical devices. In this chapter, we performed extensive blood compatibility testing of the MMM following the ISO protocol 10993-4. Our tests show that MMM has low drop in white blood cell and platelet count combined with low TAT and C5a generation. Additionally, absence of hemolysis and no significant drop in red blood cell count makes them promising candidates for application in the clinic.
In search for better sorbents which could achieve removal of a broad range of uremic toxins, Chapter 4 presents a new sorbent, CMK-3. This sorbent is developed by nanocasting methods, has dual porosity of micro- and mesopores, and therefore shows high adsorption capacity towards small water soluble toxins (creatinine (113 Da)), protein-bound molecules (indoxyl sulfate (213 Da) and hippuric acid(179 Da)), middle molecules (β2-microglobulin(11.6 kDa)) and cytokines of different sizes (IL-6 (24 kDa) and IL-8 (8 kDa)). Moreover, the performance of CMK-3 is compared with two commercially available carbon-based sorbents with predominant mesoporosity (Norit A Supra) and microporosity (Takeda 5A). Our results show that even small amounts of CMK-3 could provide effective removal of uremic toxins of various sizes and types.
In the last experimental chapter, Chapter 5, new fouling resistant membranes are developed by combining polyethersulfone (PES) and SlipSkin (SS) which is a copolymer of N-vinylpyrrolidone and n-butylmethacrylate. Our results show that a blend of PES and a small amount of SS (2 wt%) is enough to produce mechanically stable flat-sheet membranes in the low ultrafiltration range. Compared to the pristine PES and commercial Sartorius (MWCO 50 kDa) membranes, the PES/SS membranes have increased hydrophilicity ensuring high fouling resistance for both large and middle-size proteins such as bovine serum albumin (BSA) and α-Lactalbumin (LALBA), respectively.
Chapter 6 presents general conclusions and outlook of future directions in the development of better and more complete uremic toxin removal therapies.
The first successful kidney transplantation was performed 60 years ago and still remains the treatment of choice for the patients with end-stage renal disease (ESRD). Organ replacement therapy provides a better quality of life and low mortality rate, however, due to the significant lack of donor organs an average waiting time for the donor kidney varies between three and five years. During this waiting period most of the ESRD patients are strongly dependent on the dialysis treatment. The dialysis is usually performed using the hemodialysis module, which is often referred as artificial kidney.
The aim of the current project is to develop a prototype artificial kidney device which will enable prolonged and continuous removal of blood toxins. Mixed matrix membranes (MMM) will be employed as a concept in order to achieve beneficial combination of adsorption and filtration in one step. Various polymers will be investigated as the membrane forming material and different types of the sorbents (activated carbon, zeolites, urea sorbents) will be incorporated in the membrane matrix.
Pictures are adopted from: Tijink, M. S. L., et al. (2013). Biomaterials 34(32): 7819-7828
The project is the part of EU Marie Curie Innovative training network (ITN) entitled “BIOART” (FP7-PEOPLE-2012-ITN)
2013 - Present
Phd student at BST group
2011 - 2013
Erasmus Mundus Master in Membrane Engineering
2009 - 2011
MSc in Chemistry
2005 - 2009
BSc in Chemistry