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Food as medicine: targeting the uraemic phenotype in chronic kidney disease

Abstract

The observation that unhealthy diets (those that are low in whole grains, fruits and vegetables, and high in sugar, salt, saturated fat and ultra-processed foods) are a major risk factor for poor health outcomes has boosted interest in the concept of ‘food as medicine’. This concept is especially relevant to metabolic diseases, such as chronic kidney disease (CKD), in which dietary approaches are already used to ameliorate metabolic and nutritional complications. Increased awareness that toxic uraemic metabolites originate not only from intermediary metabolism but also from gut microbial metabolism, which is directly influenced by diet, has fuelled interest in the potential of ‘food as medicine’ approaches in CKD beyond the current strategies of protein, sodium and phosphate restriction. Bioactive nutrients can alter the composition and metabolism of the microbiota, act as modulators of transcription factors involved in inflammation and oxidative stress, mitigate mitochondrial dysfunction, act as senolytics and impact the epigenome by altering one-carbon metabolism. As gut dysbiosis, inflammation, oxidative stress, mitochondrial dysfunction, premature ageing and epigenetic changes are common features of CKD, these findings suggest that tailored, healthy diets that include bioactive nutrients as part of the foodome could potentially be used to prevent and treat CKD and its complications.

Key points

  • The foodome is the pool of all of the compounds that are present in a food sample and/or in a biological system that is interacting with the investigated food.

  • A food-as-medicine approach could be used as a novel strategy to utilize bioactive nutrients to target the uraemic phenotype in chronic kidney disease.

  • Epigenetic alterations, gut dysbiosis, mitochondrial dysfunction, inflammation, oxidative stress and premature ageing are common features of the uraemic phenotype that could potentially be targeted using a food-as-medicine approach.

  • Gut dysbiosis is associated with inflammation and increased cardiovascular risk; prebiotics, probiotics, synbiotics and food components, including polyphenols, sugars and proteins, could alter the diversity of the gut microbiota and the production of uraemic toxins.

  • Senotherapeutic dietary compounds could potentially mitigate the effects of premature ageing in chronic kidney disease and associated complications, such as disturbed mitochondrial metabolism.

  • Natural bioactive compounds, including those found in turmeric, broccoli sprouts, berries, propolis and other foods, are potential nutritional therapeutic agents that could modulate the expression of pro-inflammatory transcription factors and the inflammasome.

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Fig. 1: Foods that could potentially influence DNA methylation.
Fig. 2: The effect of food intake on the gut microbiota in CKD.
Fig. 3: Mechanisms by which food might modulate premature ageing in CKD.
Fig. 4: Mechanisms by which food and nutrients might affect mitochondrial function.
Fig. 5: Nutrients that activate NRF2.
Fig. 6: The effect of diet on endogenous NO.

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Acknowledgements

D.M. receives support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant no. 302034/2018-8) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, grant no. E-26/202.24/2019). P.S. receives funding from the Strategic Research Program in Diabetes at Karolinska Institutet (Swedish Research Council grant no. 2009-1068), the European Union’s Horizon 2020 research and innovation Program under the Marie Skłodowska-Curie grant agreement no. 722609; International Network for Training on Risks of Vascular Intimal Calcification and roads to Regression of Cardiovascular Disease (INTRICARE). Baxter Novum is the result of a grant from Baxter Healthcare to the Karolinska Institutet.

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D.M., N.A.B., B.L., P.G.S. and P.S. researched the data for the article. All authors contributed to discussions of the content, wrote the text and reviewed or edited the manuscript before submission.

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Correspondence to Peter Stenvinkel.

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Competing interests

B.L.’s research is funded by Baxter Healthcare. P.S. is on the scientific advisory boards of REATA, Baxter Healthcare and AstraZeneca. P.G.S. is funded through PhD studentships supported by 4D Pharma and Constant Pharma. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks N. Vaziri, A. Cupisti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Uraemic toxins

Biologically active compounds that are removed from the blood by healthy kidneys but can accumulate and exert toxic effects in the setting of kidney dysfunction.

Foodomics

The application of omics technologies to study food and nutrition.

Planetary health

The health of human civilization and the state of the natural systems on which it depends.

Methylome

The complement of methylation-based modifications in a genome or in a particular cell.

Diseaseome

The network of genes and pathways that is associated with human disease.

Osmoprotectant

Organic molecules, such as betaine, sugars and amino acids, that have neutral charge and maintain the integrity of cells exposed to osmotic stress.

One-carbon metabolism

A metabolic process that interlinks the methionine and folate cycles, which provide methyl groups for synthesis of DNA and maintenance of the epigenetic landscape.

Prebiotics

Non-digestible compounds in food that stimulate the growth of beneficial microorganisms such as bacteria and fungi.

Probiotics

Live microorganisms such as bacteria and yeasts that are thought to have health benefits when consumed.

Synbiotics

Dietary supplements that contain a combination of prebiotics and probiotics.

Salutogenic

Factors that maintain and promote human health.

Eryptosis

A type of programmed cell death that occurs in erythrocytes.

Nutraceuticals

Products derived from food that provide health benefits.

Senotherapeutics

Agents that target senescent cells, such as geroprotectors (which prevent or reverse the senescent state), senescence-associated secretory phenotype inhibitors, senolytics (which induce the death of senescent cells), senomorphics (which suppress senescent phenotypes without killing cells) and gene therapy strategies (which increase resistance to ageing).

Inflammageing

Inflammation that occurs during ageing or age-related diseases.

Blue zones

Regions in the world where people have high life expectancy, such as Okinawa (Japan), Loma Linda (USA), Sardinia (Italy), Nicoya (Costa Rica) and Icaria (Greece).

Kimchi

A traditional, heavily seasoned Korean dish made with vegetables such as napa cabbage and radish that are fermented by mainly lactic acid bacteria.

Natto

A traditional Japanese dish made with soybeans that are fermented by Bacillus subtilis.

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Mafra, D., Borges, N.A., Lindholm, B. et al. Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nat Rev Nephrol 17, 153–171 (2021). https://doi.org/10.1038/s41581-020-00345-8

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