Uremic Toxins in Organ Crosstalk

Abstract

Many putative uremic toxins—like indoxyl sulfate, p-cresol sulfate, kynurenic acid, uric acid, and CMPF—are organic anions. Both inter-organ and inter-organismal communication are involved. For example, the gut microbiome is the main source of indole, which, after modification by liver drug metabolizing enzymes (DMEs), becomes indoxyl sulfate. Various organic anion transporters (organic anion transporters, OATs; organic anion-transporting polypeptides, OATPs; multidrug resistance-associated proteins, MRPs, and other ABC transporters like ABCG2)—often termed “drug transporters”—mediate movement of uremic toxins through cells and organs. In the kidney proximal tubule, critical roles for OAT1 and OAT3 in regulating levels of protein-bound uremic toxins have been established using knock-out mice. OATs are important in maintaining residual tubular function in chronic kidney disease (CKD); as CKD progresses, intestinal transporters like ABCG2, which extrude urate and other organic anions into the gut lumen, seem to help restore homeostasis. Uremic toxins like indoxyl sulfate also regulate signaling and metabolism, potentially affecting gene expression in extra-renal tissues as well as the kidney. Focusing on the history and evolving story of indoxyl sulfate, we discuss how uremic toxins appear to be part of an extensive “remote sensing and signaling” network—involving so-called drug transporters and drug metabolizing enzymes which modulate metabolism and signaling. This systems biology view of uremic toxins is leading to a new appreciation of uremia as partly due to disordered remote sensing and signaling mechanisms–resulting from, and causing, aberrant inter-organ (e.g., gut-liver- kidney-CNS) and inter-organismal (e.g., gut microbiome-host) communication.

What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis

“…In this way, transporters, drug metabolizing enzymes (DMEs) and nuclear receptors regulate metabolic pathways, signaling, and oxidative state within and between cells, tissues, organs and organisms (e.g., gut microbes–host). Although the focus in this article as well as in other reviews on the RSST as applied to CKD [ 17 , 110 ] is on understanding the central role of transporters, DMEs and nuclear receptors in uremic metabolism, it is to be emphasized that the RSS theory is a general theory of small molecule communication between cells, tissues, organs, and organisms ( Figure 4 ) [ 16 ].…”

“…In the case of indoxyl sulfate, there appears to be a pathway from gut microbes to liver DMEs to RSS in proximal tubule cells in the service of maintaining homeostasis via effects on metabolism, redox state and signaling events [ 17 , 118 ]. This suggests how uremic compounds, while potentially toxic at high concentrations in the setting of kidney disease, may otherwise subserve important normal physiological functions [ 14 , 110 , 111 , 112 , 113 ].…”

Interorgan crosstalk mechanisms in disease: the case of acute kidney injury‐induced remote lung injury

“…More recent evidence points to a potential role of uraemic toxins in this process (reviewed in Ref. [71,72]). Indole is produced by intestinal bacteria as a degradation product of the amino acid tryptophan and is subsequently metabolized in the liver to indoxyl sulphate.…”

Acute Kidney Injury and Organ Dysfunction: What Is the Role of Uremic Toxins?

“…IS is a low-molecular-weight uremic toxin product of tryptophan metabolism that has kidney clearance by proximal tubule secretion via organic anion transporters (OAT1 and 3), thus accumulating in states of AKI and CKD [47,48]. Values higher than 2.74 µg/mL have been clinically associated with 90-day mortality after hospital-acquired AKI [49,50].…”