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Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling

Nature Reviews Nephrology volume 15, pages 301–316 (2019)Cite this article

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Abstract

Uraemic syndrome (also known as uremic syndrome) in patients with advanced chronic kidney disease involves the accumulation in plasma of small-molecule uraemic solutes and uraemic toxins (also known as uremic toxins), dysfunction of multiple organs and dysbiosis of the gut microbiota. As such, uraemic syndrome can be viewed as a disease of perturbed inter-organ and inter-organism (host–microbiota) communication. Multiple biological pathways are affected, including those controlled by solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes, many of which are also involved in drug absorption, distribution, metabolism and elimination (ADME). The remote sensing and signalling hypothesis identifies SLC and ABC transporter-mediated communication between organs and/or between the host and gut microbiota as key to the homeostasis of metabolites, antioxidants, signalling molecules, microbiota-derived products and dietary components in body tissues and fluid compartments. Thus, this hypothesis provides a useful perspective on the pathobiology of uraemic syndrome. Pathways considered central to drug ADME might be particularly important for the body’s attempts to restore homeostasis, including the correction of disturbances due to kidney injury and the accumulation of uraemic solutes and toxins. This Review discusses how the remote sensing and signalling hypothesis helps to provide a systems-level understanding of aspects of uraemia that could lead to novel approaches to its treatment.

Key points

  • The uraemic syndrome (also known as uremic syndrome) associated with chronic kidney disease (CKD) is characterized by complex local and systemic derangements in metabolism and signalling.

  • CKD involves aberrant inter-organ (gut–liver–kidney–brain) and inter-organism (host–gut microbiota) remote communication via small molecules, including uraemic solutes, metabolites and signalling molecules.

  • Aspects of uraemic syndrome can be considered disordered remote sensing and signalling mediated by a multi-organ network of solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes (DMEs).

  • The remote sensing and signalling hypothesis provides a systems biology framework for understanding the role of these transporters and DMEs in small-molecule-mediated inter-organ and inter-organism communication.

  • Transported uraemic solutes (including gut-microbiota-derived indoxyl sulfate) can affect multiple signalling pathways.

  • Viewing CKD and uraemic syndrome through the lens of the remote sensing and signalling hypothesis provides fresh perspectives on the metabolic derangements of CKD that might lead to novel therapies.

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Fig. 1: Aberrant inter-organ and inter-organism communication contributes to uraemic syndrome.
Fig. 2: The gut–liver–kidney axis.
Fig. 3: The role of indoxyl sulfate in inter-organism and inter-organ remote communication.
Fig. 4: A remote sensing and signalling system maintains homeostasis in the steady state and resets homeostasis following perturbations due to kidney dysfunction and microbiota dysbiosis.

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Acknowledgements

The authors’ work referred to in this Review was partly supported by US National Institutes of Health grants DK109392 and HD090259 (U54) to S.K.N.

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Nature Reviews Nephrology thanks T. D. Nolin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

    Sanjay K. Nigam & Kevin T. Bush

  2. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Sanjay K. Nigam

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Nigam, S.K., Bush, K.T. Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling. Nat Rev Nephrol 15, 301–316 (2019). https://doi.org/10.1038/s41581-019-0111-1

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