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8. Biofluid optics

8.1 On-line monitoring of uremic toxins

The aim is to develop a novel optical technology for monitoring of uremic toxins (UTox) related to malnutrition-inflammation syndrome on the end stage renal disease patients and to cardiovascular disease (CVD), helping doctors to improve the life quality of the patients, and decrease hospitalisations and interventions. The uremic toxins are classified as: (i) small, (ii) middle and (iii) protein bound.

The optical monitoring possibilities of all three uremic toxins group were investigated in the spent dialysate resulting:

·        the novel algorithms for measuring concentration of the following UTox and clinically related parameters: (i) urea [6], creatinine (nutritional status) [7], uric acid [1, 4], phosphate (CVD markers) [5]; (ii) middle UTox 2-microglobulin (inflammation marker) [9]; (iii) protein bound UTox indoxyl sulfate (IS) (potential inflammation and CVD marker) [2]. Unique method compared to earlier known state of the art for determining middle and protein bound uremic toxins in the spent dialysate utilizing fluorescence spectroscopy was proposed, which was a base for the Estonian and international PCT patent applications (see list of patents and pat. applications).

·        a new approach by Combining Assessment of Small Molecule Uremic Markers in order to improve Prediction of Dialysis Patients’ Survival was presented [3];

·        the first time an optical on-line method for urea rebound estimation was proposed [8].

Implementation:  Developed and designed a new prototype device for optical multicomponent dialysis monitoring.

Cooperation: Centre of Nephrology, North-Estonian Medical Centre, Tallinn (Estonia), Linköping University Hospital, Linköping (Sweden), for Molecular Cardio-vascular Research, RWTH Aachen, (Germany).

PhD thesis: J. Holmar (10.10.2013)

PhD students: R. Tomson (expected defence in 2017)

Publications:

1.      Holmar, Jana; Fridolin, Ivo; Uhlin, Fredrik; Luman, Merike; Fernström, Anders. (2013). Serum Uric Acid Level and Long Term Survival in Dialysis Patients. In: Nephrology Dialysis Transplantation: 50th ERA-EDTA Congress, Istanbul, Turkey, May 18-21, 2013.  Oxford University Press, 2013, 150.

2.      Holmar, Jana; Uhlin, Fredrik; Ferenets, Rain; Lauri, Kai; Tanner, Risto; Arund, Jürgen; Luman, Merike; Fridolin, Ivo. (2013). Estimation of Removed Uremic Toxin Indoxyl Sulphate during Hemodialysis by Using Optical Data of the Spent Dialysate. In: Proceedings of 35th Annual International Conference of the IEEE EMBS: 35th Annual International Conference of the IEEE EMBS, Osaka, Japan, 3 - 7 July, 2013.  IEEE, 2013, 6707 - 6710.

3.      Holmar, J; Fridolin, I; Uhlin, F; Fernström, A; Luman, M. (2014). Estimation of dialysis patients’ survival through combined approach of small molecule uremic markers. Proceedings of the Estonian Academy of Sciences, 63, 227 - 233.

4.      Holmar, J; Fridolin, I; Uhlin, F; Luman, M; Fernström, A. (2014). Uric Acid Level And Cardiovascular Disease In Dialysis Patients. 5th Meeting of Uremic Toxins and Cardiovascular Disease, Prague, Czech Republic, June 27-29, 2014

5.      Holmar, Jana; Uhlin, Fredrik; Fernström, Anders; Luman, Merike; Jankowski, Joachim; Fridolin, Ivo. 2015. "An Optical Method for Serum Calcium and Phosphorus Level Assessment during Hemodialysis." Toxins 7, no. 3: 719-727.

6.      R. Tomson, F. Uhlin, I. Fridolin. (2014) Urea rebound assessment based on UV-absorbance in spent dialysate. ASAIO Journal. 60(4):459-465, July/August 2014.

7.      Tomson, R.; Fridolin, I.; Luman, M. (2014). Lean Body Mass Assessment Based on UV-absorbance in Spent Dialysate. The 14th Biennial Baltic Electronics Conference, October 6-8, 2014, Tallinn, Estonia. IEEE, 2014. [forthcoming]

8.      Tomson, R.; Uhlin, F.; Fridolin, I. (2014). Optical Urea Rebound Estimation During Dialysis. In: IFMBE Proceedings: 16th Nordic-Baltic Confrence on Biomedical Engineering, October 14-16, 2014, Göteborg, Sweden.  Springer, 2014, 109 - 112.

9.      Uhlin, F; Uhlin, P; Holmar, J; Fridolin, I; Luman, M; Fernström, A. (2015). „Optical Estimation of Beta 2 Microglobulin During Hemodiafiltration – Does it Work? “ Blood Purification, [Accepted]

 

8.2 Analysis of uremic toxins- cardiovascular disease markers

No standard laboratory analyses are available for a number of protein bound and small uremic toxins' measurements in the biological fluids so far. Many of the uremic toxins are candidates being cardiovascular disease and inflammation markers. For this reason an appropriate high performance liquid chromatography (HPLC) and LC-MS method, capable to identify and quantify more uremic toxins compared to existing standard laboratory methods, was developed, making it possible to:

·        confirm in addition to the state-of-the-art, that the molecular mass of the main fluorophores in the uremic fluids do not exceed 1kDa [1, 2, 4], and there is some contribution from middle-molecular uremic toxins [3, 5]. The following fluorophores in the spent dialysate were identified: IS, indole-3-acetic acid, indoxyl glucuronide, 5-hydroxyindoleacetic acid, indoleacid, vit B6 metabolites 4-pyridoxic acid, xanthurenic acid, xanthurenic acid 8-methyl ether

·        first time identify and quantify additional to uremic solutes-chromophores in the spent dialysate a medicine paracetamole and its metabolites, and show, that the medicine Paracetamol+metabolites influence optical dialysis monitoring, UA levels in the blood and elimination profile in dialysis [6];

·        confirm the hypothesis by HPLC studies, that fluorescence is scientifically valid for estimation removal of protein bound molecular weight uremic solutes [1, 2].

Cooperation: Laboratory of Chemical Physics, National Institute of Chemical Physics and Biophysics, Tallinn (Estonia), Centre of Nephrology, North-Estonian Medical Centre, Tallinn (Estonia), Linköping University Hospital, Linköping (Sweden).

PhD students: J. Arund, K. Lauri (expected defence in 2016), S. Kalle (expected defence in 2017)

Publications:

1.      Arund, J.; Tanner, R.; Fridolin, I.; Luman, M. (2014). Mapping of fluorophores in the spent dialysate: A preliminary study. 8th International Congress on Uremia Research and Toxicity, 12-15.03.2014 Okinawa, Japan

2.      Arund, Jürgen; Tanner, Risto; Fridolin, Ivo; Luman, Merike. (2014). Fluorophores responsible for the fluorescence signal in spent dialysate. 12th Conference of Baltic Societies of Nephrology, June 12-14 2014, Dubingiai, Molėtai district, Lithuania. 2014.

3.      Kalle, S; Kressa, H; Tanner, R; Holmar, J; Fridolin, I. (2014). Long wavelength fluorescence of the spent dialysate. In: Teaduskonverentsi teesid: 12th Conference of Baltic Societies of Nephrology, Leedu, 12-14.06.2014. , 2014.

4.      Kalle, S.; Kressa, H.; Tanner, R.; Holmar, J.; Fridolin, I. (2014). Fluorescent compounds in spent dialysate. In: Teaduskonverentsi teesid: 5th meeting „Uremic toxins and Cardiovascular Disease", Praha, Tšehhi, 27-29.06.2014. , 2014.

5.      Kalle, S; Kressa, H; Tanner, R; Holmar, J; Fridolin, I. (2014). Fluorescence of Beta-2-microglobulin in the Spent Dialysate. In: 16th Nordic-Baltic Conference on Biomedical Engineering: Nordic-Baltic Conference on Biomedical Engineering and Medical Physics & 10th Medicinteknikdagarna, Göteborg, Sweden, 14-16.October.2014. (Toim.) Mindedal, H., Persson, M. Springer-Verlag, 2014, (IFMBE Proceedings; 48), 59 - 62.

6.      Risto Tanner, Jürgen Arund, Ivo Fridolin, and Merike Luman, “Paracetamol Interference in Uric Acid Levels in Uremic Patients Revealed by Monitoring Spent Dialysate,” ISRN Nephrology, vol. 2013, Article ID 515292, 4 pages, 2013. doi:10.5402/2013/515292.