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Obesity and the kidney: mechanistic links and therapeutic advances

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

Obesity is strongly associated with the development of diabetes mellitus and chronic kidney disease (CKD), but there is evidence for a bidirectional relationship wherein the kidney also acts as a key regulator of body weight. In this Review, we highlight the mechanisms implicated in obesity-related CKD, and outline how the kidney might modulate feeding and body weight through a growth differentiation factor 15-dependent kidney–brain axis. The favourable effects of bariatric surgery on kidney function are discussed, and medical therapies designed for the treatment of diabetes mellitus that lower body weight and preserve kidney function independent of glycaemic lowering, including sodium–glucose cotransporter 2 inhibitors, incretin-based therapies and metformin, are also reviewed. In summary, we propose that kidney function and body weight are related in a bidirectional fashion, and that this interrelationship affects human health and disease.

Key points

  • Obesity alters kidney function through multiple direct and indirect mechanisms.

  • Sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1RAs) both promote weight loss; they also stabilize kidney function through mechanisms that are independent of their effects on weight.

  • SGLT2is induce a metabolic shift towards ketogenesis, which is likely to account for sustained weight loss.

  • The beneficial effects of GLP1RAs on the kidney are not solely explained by weight loss or improvement in glycaemic control.

  • Several GLP1R dual or polyagonist agents are under evaluation with the potential to achieve greater weight loss than GLP1RAs alone.

  • Metformin increases levels of growth differentiation factor 15 (GDF15) in the kidney and circulation to activate glial cell line-derived neurotrophic factor family receptor ɑ-like (GFRAL) in the area postrema to reduce body weight.

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Fig. 1: Mechanisms of obesity-induced kidney disease.
Fig. 2: Proposed mechanisms contributing to the renoprotective effects of bariatric surgery.
Fig. 3: Mechanisms of weight loss associated with SGLT2 inhibitor use.
Fig. 4: Metformin lowers food intake and weight gain through a kidney–brain axis.

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Acknowledgements

K.Y. is supported by the University of Toronto Department of Medicine Eliot Phillipson Clinician Scientist Training Program, Clarence Henry Trelford Clinician Scientist Award in Diabetes, and a KRESCENT Postdoctoral Fellowship. The KRESCENT program is co-sponsored by the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institute of Health Research (CIHR). R.K. is supported by a CIHR graduate award and a Banting and Best Diabetes Centre graduate scholarship. D.Z.I.C. is supported by a Department of Medicine, University of Toronto Merit Award, and receives support from the CIHR, Diabetes Canada and the Heart and Stroke Richard Lewar Centre of Excellence. D.Z.I.C. is also the recipient of a CIHR-KFOC Teams Grant Award. T.K.T.L. is supported by CIHR grants (PJT 189957, PJT 183901, MRT-168045) and holds the Canada Research Chair (Tier 1) in Diabetes and Obesity at the Toronto General Hospital Research Institute & University of Toronto.

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  1. Division of Nephrology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada

    Kevin Yau & David Z. I. Cherney

  2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Kevin Yau, David Z. I. Cherney & Tony K. T. Lam

  3. Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Rachel Kuah & Tony K. T. Lam

  4. Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada

    Rachel Kuah, David Z. I. Cherney & Tony K. T. Lam

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All authors researched data for the article, contributed substantially to discussion of content, wrote the manuscript and reviewed and edited the manuscript before submission.

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D.Z.I.C. has received consulting fees or speaking honoraria or both from Janssen, Bayer, Boehringer Ingelheim-Eli, Lilly, AstraZeneca, Merck & Co Inc, Prometic and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim-Eli, Lilly, Sanofi, AstraZeneca and Merck & Co Inc. The other authors declare no competing interests.

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Yau, K., Kuah, R., Cherney, D.Z.I. et al. Obesity and the kidney: mechanistic links and therapeutic advances. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00951-7

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