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Inflammation and gut dysbiosis as drivers of CKD–MBD

Nature Reviews Nephrology volume 19, pages 646–657 (2023)Cite this article

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Abstract

Two decades ago, Kidney Disease: Improving Global Outcomes coined the term chronic kidney disease–mineral and bone disorder (CKD–MBD) to describe the syndrome of biochemical, bone and extra-skeletal calcification abnormalities that occur in patients with CKD. CKD–MBD is a prevalent complication and contributes to the excessively high burden of fractures and cardiovascular disease, loss of quality of life and premature mortality in patients with CKD. Thus far, therapy has focused primarily on phosphate retention, abnormal vitamin D metabolism and parathyroid hormone disturbances, but these strategies have largely proved unsuccessful, thus calling for paradigm-shifting concepts and innovative therapeutic approaches. Interorgan crosstalk is increasingly acknowledged to have an important role in health and disease. Accordingly, mounting evidence suggests a role for both the immune system and the gut microbiome in bone and vascular biology. Gut dysbiosis, compromised gut epithelial barrier and immune cell dysfunction are prominent features of the uraemic milieu. These alterations might contribute to the inflammatory state observed in CKD and could have a central role in the pathogenesis of CKD–MBD. The emerging fields of osteoimmunology and osteomicrobiology add another level of complexity to the pathogenesis of CKD–MBD, but also create novel therapeutic opportunities.

Key points

  • Chronic kidney disease (CKD) is associated with inflammation and oxidative stress; important contributing factors include cellular senescence, depletion of short chain fatty acids and gut barrier disruption.

  • Novel insights from osteoimmunology and osteomicrobiology call for a paradigm shift in the pathogenesis of CKD–mineral and bone disorder (MBD), as gut dysbiosis and immune cell dysfunction have emerged as important and targetable drivers of bone loss and vascular calcification.

  • Sex-steroid deprivation and hyperparathyroidism, both common in CKD, foster the trafficking of intestinal T helper 17 cells to the bone marrow, where they release IL-17 and trigger a cascade of events that culminates in bone loss.

  • Local and systemic oxidative stress and inflammation induce a vicious cycle of DNA damage, cell death, premature senescence and further inflammation, which are all major drivers of osteochondrogenic differentiation in vascular smooth muscle cells, ultimately resulting in vascular calcification.

  • Few studies have assessed the effects of therapies targeting either the immune system or gut microbial ecosystem on hard CKD–MBD outcomes.

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Fig. 1: Paradigm shift in the pathogenesis of CKD–MBD.
Fig. 2: Gut dysbiosis, leaky gut and inflammation in CKD.
Fig. 3: Inflammation and the calcification paradox.

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Acknowledgements

The work was supported by the Heart and Lung Foundation (P.S.), CIMED (P.S.) and Swedish Research Council (P.S.).

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Authors and Affiliations

  1. Laboratory of Nephrology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Herestraat, Leuven, Belgium

    Pieter Evenepoel

  2. Department of Renal Medicine M99, Karolinska University Hospital, Stockholm, Sweden

    Peter Stenvinkel

  3. British Heart Foundation Centre of Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London, UK

    Catherine Shanahan

  4. Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory Microbiome Research Center, and Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, GA, USA

    Roberto Pacifici

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Glossary

Postbiotics

Soluble factors (metabolic products or byproducts) that are secreted by live microbiota or released after microbial lysis, and provide physiological benefits to the host.

Prebiotics

Nutrients that promote the growth of beneficial gut microbiota.

Probiotics

Live microbiota that provide health benefits to the host when ingested.

Synbiotics

Combinations of prebiotics and probiotics.

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Evenepoel, P., Stenvinkel, P., Shanahan, C. et al. Inflammation and gut dysbiosis as drivers of CKD–MBD. Nat Rev Nephrol 19, 646–657 (2023). https://doi.org/10.1038/s41581-023-00736-7

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