Protein-Bound Uremic Toxins (PBUTs) and Cellular Transporters: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Pathology
Contributor:
Andrea Stinghen

Uremic toxins are a heterogeneous group of molecules that accumulate in the body due to the progression of chronic kidney disease (CKD), being only partially eliminated by dialysis therapies. Several uremic toxins bind to albumin and also enter cells via membrane transporters, triggering pathophysiological processes.

  • uremic toxins
  • albumin
  • cell transporters

1. Introduction

Kidney diseases were the 10th leading cause of death worldwide in 2019, according to the World Health Organization (WHO). Their mortality rate has increased approximately 37.4% in 19 years. One of the main consequences of the loss of renal function is an accumulation of uremic toxins in the body, affecting the various tissues and organs, including the cardiovascular system [1]. The biological effects promoted by uremic toxins depend on the relationship between production, degradation, and excretion, in addition to cytoplasmic distribution and the presence of inhibiting or promoting agents of the toxin’s action [2].
The European Uremic Toxin Work Group (EUTox) reports that uremic toxins can be classified into three groups due to their physicochemical characteristics and their behavior during dialysis [1]: (I) Small-water soluble compounds (molecular weight <500 Da), such as creatinine and urea; (II) Medium compounds (peptides with molecular weight >500 Da), such as cystatin-C and β2-microglobulin, which can only be removed by large pore size dialysis membranes; and (III) Protein-bound uremic toxins (PBUTs), such as indoles and phenols, which come from dietary amino acid metabolism and are poorly filtered by the dialytic membrane.
Most of the small-water soluble compounds are well known, and some can be used in the diagnosis of kidney diseases, such as serum creatinine and blood urea nitrogen (BUN) which are classic biomarkers in the progress of chronic kidney disease (CKD). Trimethylamine-N-oxide (TMAO) is in this same group, a uremic toxin associated with an increased risk of developing cardiovascular diseases (CVD), including cardiac dysfunction and atherosclerosis [3][4]. Another small-water soluble compound is inorganic phosphorus (Pi), which may not be considered as uremic toxin for some authors, but has a clear role in CVD progression. Hyperphosphatemia has been associated with accelerating the progress of renal dysfunction and is also correlated with a higher mortality rate from CVD and peripheral and visceral vascular calcification [2].
It is important to mention fibroblast growth factor 23 (FGF-23), β2-microglobulin, parathyroid hormone (PTH), and pro-inflammatory molecules such as interleukin-6 (IL-6) among the medium compounds [5][6]. High levels of these toxins contribute to progressive renal structural damage; however, they are fundamental to mineral homeostasis maintenance in a healthy organism.
PBUTs stand out for their high affinity for proteins, particularly serum albumin, making their removal by dialysis therapies difficult. Tubular secretion plays a key role in the renal elimination of these uremic toxins, with the residual renal function being an important factor in uremic levels in patients with advanced CKD [7]. Regarding PBUTs, it is important to highlight that there are few studies that have addressed these molecules, and they demand attention from the scientific community due to their behavior during dialysis, for example [5][8][9].

2. Protein-Bound Uremic Toxins (PBUTs)

2.1. Indoxyl Sulfate (IS)

Indoxyl sulfate (IS) constitutes one PBUT and is a product of the bacterial metabolism of dietary tryptophan by bacteria in the gut and converted to indole, which crosses the intestinal barrier and reaches the liver where it is converted to indoxyl, and later sulfated to IS ions, in the way it is found in the bloodstream and tissue of patients with compromised renal function [10][11][12]. About 90% of it in blood plasma is primarily bound to serum proteins such as albumin, and this binding causes its excretion to primarily occur by proximal tubular secretion and then by glomerular filtration [13].
Patients with CKD have a total IS concentration surpassing 500 μM compared to 0.1–2.39 μM in patients with healthy kidney functions [14]. As previously mentioned, the dialytic membrane pores do not effectively remove IS since 90% of it is bound to serum albumin, making the complex too large to be filtered. This retention is associated with diverse harmful effects in other organs, such as alterations to thyroid function, endothelial dysfunction, smooth muscle cell proliferation, and atherosclerosis [15][16]. IS is related to many harmful effects to the organism, with a hypertrophic effect in cardiomyocytes through the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways among them, in turn indicating that this toxin has a crucial role in developing cardiac hypertrophy under uremic conditions [17][18]. Another effect of IS is the activation of proinflammatory macrophages which generate an immune dysfunction. This activation is mediated by the uptake through transporters, including OATP2B1, which is an important mediator of inflammatory process signaling [19].

2.2. p-Cresyl Sulfate (PCS)

p-Cresyl Sulfate (PCS) is another PBUT generated from the metabolism of tyrosine and phenylalanine, two aromatic amino acids which are metabolized by bacteria from intestines. This molecule has a low molecular weight (108 Da), as with IS [2][5]. p-Cresol suffers sulfation and glucuronidation in the mucosa in the distal part of the colon of the large intestine and liver in the degradation process, generating PCS and p-cresyl-glucoronate [20]. As p-cresol is promptly metabolized, uremic patients show normal levels of these compounds similar to healthy people. Thus, PCS is the conjugated form of p-cresol with evident retention in the bloodstream of patients with CKD [21]. Serum concentration rates range from 2.8 ± 1.7 mg/L (14.9 ± 9.0 µM) 7 and 6.6 ± 3.7 mg/L (35.1 ± 19.7 µM) in patients without serious renal impairment. These concentrations in patients with end-stage CKD can range from 21.8 ± 12.4 mg/L (115.8 ± 65.9 µM) to 106.9 ± 44.6 mg/L (568.0 ± 237.0 µM), both quantified by UPLC in serum and LC-MS-MS in plasma, respectively [20][21].
Several studies point out the damage caused by PCS accumulation, such as smooth muscle cell lesions, endothelial dysfunction, coagulation disturbances, leukocyte activation, cardiac fibrosis, and metabolic disorders, including insulin resistance [21][22]. Other works have shown a deleterious effect of PCS in specific renal and cardiac cells, contributing to decrease glutathione levels promoting redox unbalance [23]. Consequently, it is possible to observe cardiac dysfunction, facilitating cardiomyocyte apoptosis and mitochondrial hyperfusion [8][24]. All effects demonstrate that this compound is linked to cardiovascular damage and contributes to the increase in mortality and cardiovascular events in CKD [2][25].

2.3. Indole-3-Acetic Acid (IAA)

In addition to IS, indole-3-acetic acid (IAA) is a PBUT derived from the gut metabolism of dietary tryptophan with a molecular weight of 264.27 Da [26][27]. Tryptophan-derived uremic toxins are agonists of the aryl hydrocarbon receptor (AhR) complex, and their accumulation in patients with CKD may activate the AhR [28], which leads to pro-oxidant, pro-inflammatory, pro-coagulant, and pro-apoptotic effects. IAA can also induce cyclooxygenase-2, worsening the inflammatory state and increasing oxidative stress [29].
Beyond the classic and canonical actions of AhR activation, the non-canonical AhR signaling after IS or IAA stimulation is responsible for blocking the cell cycle and suppressing the S-phase genes. Some studies have shown the potential carcinogenesis control combined with an increase in inflammatory cytokine expression through NF-kB. Moreover, the activation of AhR can also promote proteolysis of the endoplasmic reticulum (ER), assembling the ubiquitin ligase complex [30].
IAA has been found to stimulate glomerular sclerosis and interstitial fibrosis, accelerating renal damage and the progression of CKD [31]. In a study with transplanted and non-transplanted patients with CKD, Liabeuf et al. (2020) demonstrated that free and total IAA gradually increased with CKD progression and that IAA levels were elevated at the transplant time but substantially decreased one month after transplantation [26]. Moreover, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort [26].

2.4. 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)

3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) is one of the major metabolites of furan fatty acids and shows incredible protein-binding affinity reaching almost 100% binding with site I of albumin; thus, it is not removed by conventional dialysis therapies [32][33]. CMPF plasma levels can remain high even 90 days after a successful kidney transplant [34]. The source of elevated levels of circulating CMPF is still unknown, and the consequences of its accumulation are still unclear [35][36]. However, it was demonstrated that CMPF is elevated in diabetes and acts directly in β cells, dysregulating key transcription factors, eventually leading to reduced insulin biosynthesis, and inducing oxidative stress [37]. CMPF in CKD directly interacts with oxygen radicans and can enhance the production of reactive oxygen species (ROS) in HK-2 cells and consequently induce cell damage [38]. Given its role in oxidative stress, CMPF is often associated with uremic toxins with cardiovascular relevance [39][40]. However, a study conducted by Luce et al. (2018) with patients in hemodialysis showed that elevated serum CMPF levels were not associated with mortality or cardiovascular mortality in that cohort but were positively correlated with nutritional parameters and lean mass and is significantly elevated in patients without protein-energy wasting [41].

3. Cell Membrane Transporters of Uremic Toxins

Uremic toxins interact with membrane transporters, proteins which mediate the influx or efflux of these compounds into the cell. These toxins can activate signaling pathways upon entering the cell and modulate the cellular response under uremic conditions, contributing to the pathological process of CKD. The transport of uremic toxins across the cell membrane has been associated with representatives of the solute carrier (SLC) transporter and ATP-binding cassette (ABC) transporter superfamilies, which are known to transport a variety of endogenous and xenobiotic compounds, and are also implicated in drug therapy. Importantly, membrane transporters are essential for the renal elimination of these compounds via tubular secretion.

This entry is adapted from the peer-reviewed paper 10.3390/toxins14030177

References

  1. Vanholder, R.; De Smet, R.; Glorieux, G.; Argilés, A.; Baurmeister, U.; Brunet, P.; Clark, W.; Cohen, G.; De Deyn, P.P.; Deppisch, R.; et al. Review on uremic toxins: Classification, concentration, and interindividual variability. Kidney Int. 2003, 63, 1934–1943.
  2. Falconi, C.A.; da Cruz Junho, C.V.; Fogaça-Ruiz, F.; Vernier, I.C.S.; da Cunha, R.S.; Stinghen, A.E.M.; Carneiro-Ramos, M.S. Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System. Front. Physiol. 2021, 12, 114460.
  3. Li, X.S.; Obeid, S.; Klingenberg, R.; Gencer, B.; Mach, F.; Räber, L.; Windecker, S.; Rodondi, N.; Nanchen, D.; Muller, O.; et al. Gutmicrobiota-dependent trimethylamine N-oxide in acute coronary syndromes: A prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur. Heart J. 2017, 38, 814–824.
  4. Stubbs, J.R.; House, J.A.; Ocque, A.J.; Zhang, S.; Johnson, C.; Kimber, C.; Schmidt, K.; Gupta, A.; Wetmore, J.B.; Nolin, T.D.; et al. Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden. J. Am. Soc. Nephrol. 2016, 27, 305–313.
  5. Barreto, F.C.; Stinghen, A.E.M.; De Oliveira, R.B.; Franco, A.T.B.; Moreno, A.N.; Barreto, D.V.; Pecoits-Filho, R.; Drüeke, T.B.; Massy, Z.A. The quest for a better understanding of chronic kidney disease complications: An update on uremic toxins. J. Bras. Nefrol. 2014, 36, 221–235.
  6. Massy, Z.A.; Liabeuf, S. Middle-molecule uremic toxins and outcomes in chronic kidney disease. Contrib. Nephrol. 2017, 191, 8–17.
  7. Van Gelder, M.K.; Middel, I.R.; Vernooij, R.W.M.; Bots, M.L.; Verhaar, M.C.; Masereeuw, R.; Grooteman, M.P.; Nubé, M.J.; van den Dorpel, M.A.; Blankestijn, P.J.; et al. Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome. Toxins 2020, 12, 234.
  8. Han, H.; Zhu, J.; Zhu, Z.; Ni, J.; Du, R.; Dai, Y.; Chen, Y.; Wu, Z.; Lu, L.; Zhang, R. p-Cresyl Sulfate Aggravates Cardiac Dysfunction Associated with Chronic Kidney Disease by Enhancing Apoptosis of Cardiomyocytes. J. Am. Heart Assoc. 2015, 4, e001852.
  9. Calaf, R.; Cerini, C.; Génovésio, C.; Verhaeghe, P.; Jourde-Chiche, N.; Bergé-Lefranc, D.; Gondouin, B.; Dou, L.; Morange, S.; Argilés, A.; et al. Determination of uremic solutes in biological fluids of chronic kidney disease patients by HPLC assay. J. Chromatogr. B 2011, 879, 2281–2286.
  10. Niwa, T. Uremic toxicity of indoxyl sulfate. Nagoya J. Med. Sci. 2010, 72, 1–11.
  11. Ito, S.; Yoshida, M. Protein-bound uremic toxins: New culprits of cardiovascular events in chronic kidney disease patients. Toxins 2014, 6, 665–678.
  12. Barreto, F.C.; Barreto, D.V.; Liabeuf, S.; Meert, N.; Glorieux, G.; Temmar, M.; Choukroun, G.; Vanholder, R.; Massy, Z.A. Serum Indoxyl Sulfate Is Associated with Vascular Disease and Mortality in Chronic Kidney Disease Patients. Clin. J. Am. Soc. Nephrol. 2009, 4, 1551–1558.
  13. Lekawanvijit, S. Cardiotoxicity of uremic toxins: A driver of cardiorenal syndrome. Toxins 2018, 10, 352.
  14. Gao, H.; Liu, S. Role of uremic toxin indoxyl sulfate in the progression of cardiovascular disease. Life Sci. 2017, 185, 23–29.
  15. Da Cunha, R.S.; Santos, A.F.; Barreto, F.C.; Stinghen, A.E.M. How do Uremic Toxins Affect the Endothelium? Toxins 2020, 12, 412.
  16. Lekawanvijit, S.; Adrahtas, A.; Kelly, D.J.; Kompa, A.R.; Wang, B.H.; Krum, H. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur. Heart J. 2010, 31, 1771–1779.
  17. Kim, H.Y.; Yoo, T.-H.; Cho, J.-Y.; Kim, H.C.; Lee, W.-W. Indoxyl sulfate–induced TNF-α is regulated by crosstalk between the aryl hydrocarbon receptor, NF-κB, and SOCS2 in human macrophages. FASEB J. 2019, 33, 10844–10858.
  18. Yang, K.; Wang, C.; Nie, L.; Zhao, X.; Gu, J.; Guan, X.; Wang, S.; Xiao, T.; Xu, X.; He, T.; et al. Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy. J. Am. Soc. Nephrol. 2015, 26, 2434–2446.
  19. Nakano, T.; Katsuki, S.; Chen, M.; Decano, J.L.; Halu, A.; Lee, L.H.; Pestana, D.V.S.; Kum, A.S.T.; Kuromoto, R.K.; Golden, W.S.; et al. Uremic Toxin Indoxyl Sulfate Promotes Proinflammatory Macrophage Activation Via the Interplay of OATP2B1 and Dll4-Notch Signaling. Circulation 2019, 139, 78–96.
  20. Gryp, T.; Vanholder, R.; Vaneechoutte, M.; Glorieux, G. p-Cresyl Sulfate. Toxins 2017, 9, 52.
  21. Vanholder, R.; Schepers, E.; Pletinck, A.; Nagler, E.V.; Glorieux, G. The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate: A Systematic Review. J. Am. Soc. Nephrol. 2014, 25, 1897–1907.
  22. Gondouin, B.; Cerini, C.; Dou, L.; Sallée, M.; Duval-Sabatier, A.; Pletinck, A.; Calaf, R.; Lacroix, R.; Jourde-Chiche, N.; Poitevin, S.; et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int. 2013, 84, 733–744.
  23. Edamatsu, T.; Fujieda, A.; Itoh, Y. Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells. PLoS ONE 2018, 13, e0193342.
  24. Huang, T.H.; Yip, H.K.; Sun, C.K.; Chen, Y.L.; Yang, C.C.; Lee, F.Y. P-cresyl sulfate causes mitochondrial hyperfusion in H9C2 cardiomyoblasts. J. Cell. Mol. Med. 2020, 24, 8379–8390.
  25. Glorieux, G.; Vanholder, R.; Van Biesen, W.; Pletinck, A.; Schepers, E.; Neirynck, N.; Speeckaert, M.; De Bacquer, D.; Verbeke, F. Free p-cresyl sulfate shows the highest association with cardiovascular outcome in chronic kidney disease. Nephrol. Dial. Transplant. 2021, 36, 998–1005.
  26. Liabeuf, S.; Laville, S.M.; Glorieux, G.; Cheddani, L.; Brazier, F.; Beauport, D.T.; Valholder, R.; Choukroun, G.; Massy, Z.A. Difference in profiles of the gut-derived tryptophan metabolite indole acetic acid between transplanted and non-transplanted patients with chronic kidney disease. Int. J. Mol. Sci. 2020, 21, 2031.
  27. Rysz, J.; Franczyk, B.; Ławiński, J.; Olszewski, R.; Ciałkowska-Rysz, A.; Gluba-Brzózka, A. The Impact of CKD on Uremic Toxins and Gut Microbiota. Toxins 2021, 13, 252.
  28. Dou, L.; Poitevin, S.; Sallée, M.; Addi, T.; Gondouin, B.; McKay, N.; Denison, M.S.; Jourde-Chiche, N.; Duval-Sabatier, A.; Cerini, C.; et al. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int. 2018, 93, 986–999.
  29. Dou, L.; Sallée, M.; Cerini, C.; Poitevin, S.; Gondouin, B.; Jourde-Chiche, N.; Fallague, K.; Brunet, P.; Calaf, R.; Dussol, B.; et al. The cardiovascular effect of the uremic solute indole-3 acetic acid. J. Am. Soc. Nephrol. 2015, 26, 876–887.
  30. Lamas, B.; Natividad, J.M.; Sokol, H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018, 11, 1024–1038.
  31. Satoh, M.; Hayashi, H.; Watanabe, M.; Ueda, K.; Yamato, H.; Yoshioka, T.; Motojima, M. Uremic Toxins Overload Accelerates Renal Damage in a Rat Model of Chronic Renal Failure. Nephron Exp. Nephrol. 2003, 95, e111–e118.
  32. Meijers, B.K.I.; Bammens, B.; Verbeke, K.; Evenepoel, P. A review of albumin binding in CKD. Am. J. Kidney Dis. 2008, 51, 839–850.
  33. Sakai, T.; Takadate, A.; Otagiri, M. Characterization of Binding Site of Uremic Toxins on Human Serum Albumin. Biol. Pharm. Bull. 1995, 18, 1755–1761.
  34. Mabuchi, H.; Nakahashi, H.; Hamajima, T.; Aikawa, I.; Oka, T. The Effect of Renal Transplantation on a Major Endogenous Ligand Retained in Uremic Serum. Am. J. Kidney Dis. 1989, 13, 49–54.
  35. Koppe, L.; Poitout, V. CMPF: A Biomarker for Type 2 Diabetes Mellitus Progression? Trends Endocrinol. Metab. 2016, 27, 439–440.
  36. Xu, L.; Sinclair, A.J.; Faiza, M.; Li, D.; Han, X.; Yin, H.; Wang, Y. Furan fatty acids—Beneficial or harmful to health? Prog. Lipid Res. 2017, 68, 119–137.
  37. Prentice, K.J.; Luu, L.; Allister, E.M.; Liu, Y.; Jun, L.S.; Sloop, K.W.; Hardy, A.B.; Wei, L.; Jia, W.; Fantus, I.G.; et al. The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell Metab. 2014, 19, 653–666.
  38. Miyamoto, Y.; Iwao, Y.; Mera, K.; Watanabe, H.; Kadowaki, D.; Ishima, Y.; Chuang, V.T.G.; Sato, K.; Otagiri, M.; Maruyama, T. A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate. Biochem. Pharmacol. 2012, 84, 1207–1214.
  39. Wratten, M.L.; Galaris, D.; Tetta, C.; Sevanian, A. Evolution of oxidative stress and inflammation during hemodialysis and their contribution to cardiovascular disease. Antioxid. Redox Signal. 2002, 4, 935–944.
  40. Boelaert, J.; Lynen, F.; Glorieux, G.; Eloot, S.; Van Landschoot, M.; Waterloos, M.A.; Sandra, P.; Vanholder, R. A novel UPLC-MS-MS method for simultaneous determination of seven uremic retention toxins with cardiovascular relevance in chronic kidney disease patients. Anal. Bioanal. Chem. 2013, 405, 1937–1947.
  41. Luce, M.; Bouchara, A.; Pastural, M.; Granjon, S.; Szelag, J.C.; Laville, M.; Arkouche, W.; Fouque, D.; Soulage, C.O.; Koppe, L. Is 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) a clinically relevant uremic toxin in haemodialysis patients? Toxins 2018, 10, 205.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback