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Albuminuria Downregulation of the Anti-Aging Factor Klotho: The Missing Link Potentially Explaining the Association of Pathological Albuminuria with Premature Death

Abstract

Ten percent of the adult population has chronic kidney disease (CKD), which is diagnosed when the glomerular filtration rate (GFR) is below 60 mL/min per 1.73 m2 or when albuminuria is above 30 mg/day. The numerical thresholds were chosen because they are associated with an increased risk of CKD progression or premature death within a wider scenario of accelerated aging. Indeed, CKD is one of the fastest growing causes of death worldwide. A decreased GFR is associated with the accumulation of uraemic toxins that may promote tissue and organ damage. However, CKD may be diagnosed when the GFR is completely normal, as long as there is pathological albuminuria. A key unanswered question to stem the rise of CKD-associated deaths is whether the association between isolated albuminuria (when the GFR is normal) and premature death is causal. The recent demonstration that albuminuria per se directly suppresses the production of the anti-aging factor Klotho by kidney tubular cells may be one of the first steps to address the causality of the albuminuria–premature death–accelerated aging association. This hypothesis should be tested in interventional studies that should draw from translational science advances. Thus, the observation that albuminuria decreases Klotho production through epigenetic mechanisms implies that Klotho downregulation may persist after the correction of albuminuria, and innovative therapeutic approaches are needed to restore Klotho production. On the basis of recent literature, these may include manipulation of NF-kappaB regulators such as B cell lymphoma 3 protein (BCL-3), and epigenetic regulators such as histone deacetylases, or the repurposing of drugs such as pentoxifylline.

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Acknowledgements

This supplement has been funded by Kyowa Kirin.

Funding

Kyowa Kirin organized the scientific meeting and contributed to the financing of the publication of the opinion of the speakers presented at that meeting (Madrid, November 2018). Research by the authors is supported by ISCIII and FEDER funds, PI16/02057, PI15/00298, PI18/01366, Sociedad Española de Nefrología, ISCIII-RETIC REDinREN RD016/009, Comunidad de Madrid CIFRA2 B2017/BMD-3686.

Medical Writing, Editorial, and Other Assistance

The authors would like to thank Anabel Herrero PhD for providing medical writing assistance on behalf of Springer Healthcare. Kyowa Kirin funded the writing assistance provided by Springer Healthcare Ibérica SL. Ruth Blaikie provided the copy editing of this manuscript.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authors’ Contributions

Alberto Ortiz, Beatriz Fernández–Fernández, and Maria Dolores Sánchez-Niño had the idea for the article. Alberto Ortiz, Beatriz Fernández–Fernández, Maria Dolores Sánchez-Niño, and Lara Valiño-Rivas performed the literature search and data analysis. Lara Valiño-Rivas created the illustrations. All authors contributed to and approved the final version of the article. All authors had full access to the articles reviewed in this manuscript and take complete responsibility for the integrity and accuracy of this manuscript.

Disclosures

Alberto Ortiz has received speaker fees from Kyowa Kirin for different educational projects and holds patents to prevent Klotho downmodulation through the modulation of Bcl3 expression or through the use of pentoxifylline. Maria Dolores Sánchez-Niño holds patents to prevent Klotho downmodulation through the modulation of Bcl3 expression or through the use of pentoxifylline. Beatriz Fernández and Lara Valiño declare that they have no conflict of interest.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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Correspondence to Alberto Ortiz.

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Fernández-Fernández, B., Valiño-Rivas, L., Sánchez-Niño, M.D. et al. Albuminuria Downregulation of the Anti-Aging Factor Klotho: The Missing Link Potentially Explaining the Association of Pathological Albuminuria with Premature Death. Adv Ther 37, 62–72 (2020). https://doi.org/10.1007/s12325-019-01180-5

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Keywords

  • Aging
  • Albuminuria
  • Chronic kidney disease
  • Glomerular filtration rate
  • Klotho