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  • Review Article
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Targeting innate immunity-driven inflammation in CKD and cardiovascular disease

Nature Reviews Nephrology volume 18, pages 762–778 (2022)Cite this article

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Abstract

Mortality among patients with chronic kidney disease (CKD) is largely a consequence of cardiovascular disease (CVD) and is a particular concern given the increasing prevalence of CKD. Sterile inflammation triggered by activation of the innate immune system is an important driver of both CKD and associated CVD. Several endogenous mediators, including lipoproteins, crystals such as silica, urate and cholesterol crystals, or compounds released from dying cells interact with pattern recognition receptors expressed on a variety of different cell types, leading to the release of pro-inflammatory cytokines. Disturbed regulation of the haematopoietic system by damage-associated molecular patterns, or as a consequence of clonal haematopoiesis or trained innate immunity, also contributes to the development of inflammation. In observational and genetic association studies, inflammation is linked to the progression of CKD and cardiovascular events. In 2017, the CANTOS trial of canakinumab provided evidence that inhibiting inflammation driven by NLRP3–IL-1–IL-6-mediated signalling significantly reduced cardiovascular event rates in individuals with and without CKD. Other approaches to target innate immune pathways are now under investigation for their ability to reduce cardiovascular events and slow disease progression among patients with atherosclerosis and stage 3 and 4 CKD. This Review summarizes current understanding of the role of inflammation in the pathogenesis of CKD and its associated CVD, and how this knowledge may translate into novel therapeutics.

Key points

  • Sterile inflammation has an important role in the pathogenesis of chronic kidney disease (CKD) and cardiovascular disease (CVD).

  • Activation of the NLRP3 inflammasome by endogenous ligands represents an important driver of inflammation in both CKD and CVD.

  • CKD and CVD are associated with alterations in the haematopoietic system caused by changes in the haematopoietic niche, clonal haematopoiesis and trained innate immunity.

  • Epidemiological and genetic studies link inflammation with CKD progression and cardiovascular events.

  • Anti-inflammatory treatments that target the NLRP3 to IL-1 to IL-6 pathway of innate immunity, such as canakinumab and colchicine, reduce cardiovascular events, although use of colchicine may be limited for those with severe CKD.

  • Targeting inflammation represents an important therapeutic advance in CKD and CVD.

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Fig. 1: Pathways leading to activation of the NLRP3 inflammasome.
Fig. 2: Cellular signalling pathways of the cytokines IL-1α, IL-1β and IL-6.
Fig. 3: Regulation of the haematopoietic niche in the bone marrow and hierarchy of haematopoiesis.
Fig. 4: Inflammatory pathways in distinct kidney cell types that lead to kidney fibrosis and glomerular injury.
Fig. 5: Inflammation in the pathogenesis of atherosclerotic lesion formation.
Fig. 6: Trained innate immunity and clonal haematopoiesis.

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Acknowledgements

T.S., S.J.S. and D.F. are supported by the Deutsche Forschungsgemeinschaft (DFG, SFB TRR 219, Project-ID 322900939).

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Authors and Affiliations

  1. Translational Cardio-Renal Medicine, Saarland University, Homburg, Germany

    Thimoteus Speer

  2. German Center for Cardiovascular Research DZHK, Frankfurt am Main, Germany

    Stefanie Dimmeler

  3. Cardiopulmonary Institute, Goethe University Frankfurt, Frankfurt am Main, Germany

    Stefanie Dimmeler

  4. Institute of Cardiovascular Regeneration, Center of Molecular Medicine Goethe University Frankfurt, Frankfurt am Main, Germany

    Stefanie Dimmeler

  5. Department of Internal Medicine 4, Nephrology and Hypertension, Saarland University, Homburg, Germany

    Stefan J. Schunk & Danilo Fliser

  6. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Paul M Ridker

  7. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Paul M Ridker

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Competing interests

T.S. has received consulting and speaker fees from Amgen, Astellas, Bayer, GSK, Novartis, Novo Nordisk, Sanofi and Vifor. D.F. has received consulting and speaker fees from Amgen, Astellas, Bayer, Boehringer Ingelheim, GSK, Novartis, Novo Nordisk and Vifor. P.M.R. has received research grant support from Novartis, Kowa, Amarin and Pfizer, and has served as a consultant to Corvidia, Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, SOCAR, Novo Nordisk, Upton, Omeicos, Health Outlook, Montai Health and Boehringer-Ingelheim. The other authors declare no competing interests.

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Glossary

Acute phase response

Non-specific reaction of the innate immune system to infections, inflammation and tissue injury.

Residual inflammatory risk

Persisting risk of cardiovascular events due to inflammation despite high-intensity lipid-lowering therapy.

Acute phase proteins

Cytokines, chemokines and other proteins released by leukocytes and other cell types during the acute phase response.

Haematopoietic niche

A spatiotemporal compartmentalization of the bone marrow, in which resident cells, such as mesenchymal stroma cells, endothelial cells, cells of the endosteal niche and macrophages, interact with haematopoietic stem cells to orchestrate their differentiation and fate.

Mendelian randomization analyses

Epidemiological methods to assess the association between single-nucleotide polymorphisms in distinct genes and outcomes to establish a causal effect between gene and phenotype.

Phenome-wide association analyses

Epidemiological methods to assess the association between single-nucleotide polymorphisms and a large number of outcomes or phenotypes.

Carbamylation

Post-translational modification of lysine residues within proteins induced by urea or myeloperoxidase-derived cyanate, leading to the formation of carbamylated lysine, which is also referred to as homocitrulline.

Guanidinylation

Post-translational modification of lysine residues within proteins induced by guanidine or urea, leading to the formation of guanidinylated lysine, which is also referred to as homoarginine.

Reverse cholesterol transport

Transport of cholesterol from peripheral tissues by high-density lipoprotein to the liver for biliary excretion.

Epithelial-to-mesenchymal transition

Differentiation of epithelial cells to mesenchymal cells such as (myo)fibroblasts, which represents an important step in tissue fibrosis.

Synbiotics

Dietary products or supplements containing probiotics (living microorganisms) and prebiotics (supplements modulating growth and/or metabolism of microorganisms).

Prebiotics

Dietary products or supplements that modulate growth and/or metabolism of microorganisms, such as bacteria.

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Speer, T., Dimmeler, S., Schunk, S.J. et al. Targeting innate immunity-driven inflammation in CKD and cardiovascular disease. Nat Rev Nephrol 18, 762–778 (2022). https://doi.org/10.1038/s41581-022-00621-9

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