What are Protein Bound Uremic Toxins (PBUTs)?

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In the case of End-Stage Renal Disease (ESRD) patients, we typically hear about removal of organic wastes such as urea and creatinine by dialysis, whether via peritoneum or blood. With new technologies, researchers have been able to identify and characterise other types of uraemic toxins that are removed via the kidneys.

More than 30 years of research has resulted in the classification and study of over 90 uraemic toxins1. They are categorised into three major groups – the small water-soluble compounds like urea and creatinine, middle molecules and protein-bound compounds (1,2). There has been a flurry of investigations to understand how these toxins interact with the body and to find effective treatments of preventing systemic toxicity. One category that is of particular interest is the protein-bound uraemic toxins (PBUTs) as they are not as easily detected nor easily removed with kidney dialysis as they mask their presence when they bind to proteins such as albumin.

Indoxylsulfate (IS) and p-cresylsulfate (pCS) are two common PBUTs that are being studied. It has been found in rat models that the presence of these two toxins cause a stimulation of white blood cells which resulted in damaged blood vessels(3). These damages contribute to cardiovascular disease, which is a major complication for people living with chronic kidney disease. These compounds bind to albumin, a molecule that is responsible for binding to other water-insoluble drugs such as Ibuprofen and Frusemide. When there is competition occurring at the binding sites, there can be a risk of drug toxicity in the body.

Looking from a broader perspective, assessing the culprit given a clinical symptom is a complex process as there may be more than one toxin involved. A myriad of clinical symptoms such as high or low blood pressure, infection of the heart, sleep disorders, fatigue, reduced or hyper nerve sensitivities, blood disorder, reduced kidney function, risk of cancer, etc. can find its root cause in one or more uraemic toxins that the kidney or kidney replacement therapy failed to remove1.

Novel methods of removal of these toxins are being developed. The use of a charcoal absorber (4), adding competing drugs in the dialysis chamber (5) and increasing dialysis times are showing signs of removing PBUTs during haemodialysis however one has to consider the repercussions on the person in terms of quality of life and costs of treatment. Where things now stand, uraemic toxins are still being discovered and their effects on the body systems are still being studied.

With the new evidence of these newly discovered toxins and their potentially damaging effects on the kidneys and other organs, it might be time to develop new methods of testing in order to detect them more accurately and to raise awareness among the ESRD patients about the importance of clearing these toxins along with urea and creatinine.

References:

1. Lisowska-Myjak, B. (2014) Uremic toxins and their effects on multiple organ systems. Nephron Clinical Practice, 128, pp. 303-11.

2. Dhondt, A., Vanholder, R., Van Biesen, W., Lamiere, N. (2000) ‘The removal of uremic toxins’, Kidney International, 58(76), pp. 303-311.

3. Pletinck, A., Glorieux, G., Schepers, E., Cohen, G., Gondouin, B., Van Landschoot, M., … Vanholder, R. (2013) Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall. Journal of the American Society of Nephrology, 24, pp. 1981-94.

4. Yamamoto, S., Kazama, J. J., Omori, K., Matsup, K., Takahashi, Y., Kawamura, K…Narita, I. (2015) Continuous reduction of protein-bound uraemic toxins with improved oxidative stress by using the oral charcoal adsorbent AST-120 in haemodialysis patients. Scientific Reports, 5, 14381, pp. 1-8

5. Tao, X., Thijssen, S., Kotanko, P., Ho, C., Henrie, M., Stroup, E., Handelman, G. (2016) Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: An in vitro human whole blood study. Scientific Reports, 6, 23389, pp. 1-9

Author:

Sheena Gow (https://www.linkedin.com/in/sheena-gow-7a96bb135/)

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