From old uraemic toxins to new uraemic toxins: place of ‘omics’

Massy, Ziad A.; Liabeuf, Sophie

doi:10.1093/ndt/gfy212

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…Trimethylamine N-oxide (TMAO) is a gut-derived free water-soluble low-molecular-weight uremic toxin [ 82 ]. Intestinal bacteria produce trimethylamine (TMA) from dietary choline, phosphatidylcholine, L-carnitine, and betaine.…”

Section: Free Water-soluble Low-molecular-weight Uremic Toxinsmentioning

confidence: 99%

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Lim

Sidor

Tonial

et al. 2021

Toxins

195

110

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Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

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Section: Free Water-soluble Low-molecular-weight Uremic Toxinsmentioning

confidence: 99%

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Lim

Sidor

Tonial

et al. 2021

Toxins

195

110

View full text Add to dashboard Cite

show abstract

“…This compounded matters further, as an already crowded field in need of sifting became more complex towards the goal of elucidating the pathophysiology of uraemia and, in developing more specific therapy strategies. Today it is still widely acknowledged that other, probably several, URS remain unidentified [ 40 ]. It needs to be recognized, however, that the mere identification and characterization of additional ‘novel’ retention solutes—or their removal—even if shown to be highly toxic, are unlikely to help improve dialysis therapies per se .…”

Section: Solutes Retained In Uraemia—their Identitymentioning

confidence: 99%

“…Today, more powerful analytical tools facilitate the identification of these yet to be characterized substances compared with the painstakingly laborious methods of the past. Two approaches that are now being utilized in uraemic toxicity research are metabolomic and proteomic profiling of biological fluids, the former focusing on small molecules while the latter is suited for the study of peptides and proteins [ 40 , 43–45 ]. Both approaches involve highly sophisticated software-backed analytical techniques such as nuclear magnetic resonance spectroscopy and mass spectrometry.…”

Section: Solutes Retained In Uraemia—their Identitymentioning

confidence: 99%

The membrane perspective of uraemic toxins: which ones should, or can, be removed?

Bowry¹,

Kotanko

Himmele

et al. 2021

Clinical Kidney Journal

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Informed decision-making is paramount to the improvement of dialysis therapies and patient outcomes. A cornerstone of delivery of optimal dialysis therapy is to delineate which substances (uraemic retention solutes or ‘uraemic toxins’) contribute to the condition of uraemia in terms of deleterious biochemical effects they may exert. Thereafter, decisions can be made as to which of the accumulated compounds need to be targeted for removal and by which strategies. For haemodialysis (HD), the non-selectivity of membranes is sometimes considered a limitation. Yet, considering that dozens of substances with potential toxicity need to be eliminated, and targeting removal of individual toxins explicitly is not recommended, current dialysis membranes enable elimination of several molecules of a broad size range within a single therapy session. However, because HD solute removal is based on size-exclusion principles, i.e. the size of the substances to be removed relative to the mean size of the ‘pores’ of the membrane, only a limited degree of selectivity of removal is possible. Removal of unwanted substances during HD needs to be weighed against the unavoidable loss of substances that are recognized to be necessary for bodily functions and physiology. In striving to improve the efficiency of HD by increasing the porosity of membranes, there is a greater potential for the loss of substances that are of benefit. Based on this elementary trade-off and availability of recent guidance on the relative toxicity of substances retained in uraemia, we propose a new evidence-linked uraemic toxin elimination (ELUTE) approach whereby only those clusters of substances for which there is a sufficient body of evidence linking them to deleterious biological effects need to be targeted for removal. Our approach involves correlating the physical properties of retention solutes (deemed to express toxicity) with key determinants of membranes and separation processes. Our analysis revealed that in attempting to remove the relatively small number of ‘larger’ substances graded as having only moderate toxicity, uncontrolled (and efficient) removal of several useful compounds would take place simultaneously and may compromise the well-being or outcomes of patients. The bulk of the uraemic toxin load comprises uraemic toxins below <30 000 Da and are adequately removed by standard membranes. Further, removal of a few difficult-to-remove-by-dialysis (protein-bound) compounds that express toxicity cannot be achieved by manipulation of pore size alone. The trade-off between the benefits of effective removal of the bulk of the uraemic toxin load and risks (increased loss of useful substances) associated with targeting the removal of a few larger substances in ‘high-efficiency’ HD treatment strategies needs to be recognized and better understood. The removability during HD of substances, be they toxic, inert or beneficial, needs be revised to establish the pros and cons of current dialytic elimination strategies.

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“…Throughout the history and development of HD the preoccupation has been, firstly, to ascribe toxicity to substances known to be retained in uraemia and search for newer uraemic toxins using sophisticated analytical technologies [ 17 , 18 ]. Secondly, newer treatment modalities and technologies strive to decrease the concentrations of selected (unwanted) substances as efficiently as possible [ 19 , 20 ].…”

Section: Transport Of Essential Substances Into the Dialysate Compartment In Haemodialysismentioning

confidence: 99%

Clinical relevance of abstruse transport phenomena in haemodialysis

Bowry¹,

Kırçelli

Mooppil³

et al. 2021

Clinical Kidney Journal

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Haemodialysis (HD) utilizes the bidirectional properties of semipermeable membranes to remove uraemic toxins from blood while simultaneously replenishing electrolytes and buffers to correct metabolic acidosis. However, the nonspecific size-dependent transport across membranes also means that certain useful plasma constituents may be removed from the patient (together with uraemic toxins), or toxic compounds, e.g. endotoxin fragments, may accompany electrolytes and buffers of the dialysis fluids into blood and elicit severe biological reactions. We describe the mechanisms and implications of these undesirable transport processes that are inherent to all HD therapies and propose approaches to mitigate the effects of such transport. We focus particularly on two undesirable events that are considered to adversely affect HD therapy and possibly impact patient outcomes. Firstly, we describe how loss of albumin (and other essential substances) can occur while striving to eliminate larger uraemic toxins during HD and why hypoalbuminemia is a clinical condition to contend with. Secondly, we describe the origins and mode of transport of biologically active substances (from dialysis fluids with bacterial contamination) into the blood compartment and biological reactions they elicit. Endotoxin fragments activate various proinflammatory pathways to increase the underlying inflammation associated with chronic kidney disease. Both phenomena involve the physical as well as chemical properties of membranes that must be selected judiciously to balance the benefits with potential risks patients may encounter, in both the short and long term.

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From old uraemic toxins to new uraemic toxins: place of ‘omics’

Cited by 12 publications

References 36 publications

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

The membrane perspective of uraemic toxins: which ones should, or can, be removed?

Clinical relevance of abstruse transport phenomena in haemodialysis

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