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Translational Therapeutics

Dietary sodium restriction prevents vascular endothelial growth factor inhibitor-induced hypertension

British Journal of Cancer volume 128, pages 354–362 (2023)Cite this article

Subjects

Abstract

Background

Vascular endothelial growth factor inhibitors (VEGFIs) are effective anticancer agents which often induce hypertension. VEGFI-induced hypertension is sodium-sensitive in animal studies. Therefore, the efficacy of dietary sodium restriction (DSR) to prevent VEGFI-induced hypertension in cancer patients was studied.

Methods

Cancer patients with VEGFI-induced hypertension (day mean >135/85 mmHg or a rise in systolic and/or diastolic BP ≥ 20 mmHg) were treated with DSR (aiming at <4 g salt/day). The primary endpoint was the difference in daytime mean arterial blood pressure (MAP) increase between the treatment cycle with and without DSR.

Results

During the first VEGFI treatment cycle without DSR, mean daytime MAP increased from 95 to 110 mmHg. During the subsequent treatment cycle with DSR, mean daytime MAP increased from 94 to 102 mmHg. Therefore, DSR attenuated the increase in mean daytime MAP by 7 mmHg (95% CI 1.3–12.0, P = 0.009). DSR prevented the rise in the endothelin-1/renin ratio that normally accompanies VEGFI-induced hypertension (P = 0.020) and prevented the onset of proteinuria: 0.15 (0.10–0.25) g/24 h with DSR versus 0.19 (0.11–0.32) g/24 h without DSR; P = 0.005.

Discussion

DSR significantly attenuated VEGFI induced BP rise and proteinuria and thus is an effective non-pharmacological intervention.

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Fig. 1: Study design.
Fig. 2: Flow diagram screening showing included and excluded patients.
Fig. 3: Effect of dietary salt restriction on blood pressure rise.
Fig. 4: Correlation changes in endothelin (ET-1)/renin ratio and daytime mean arterial pressure (MAP).

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Data availability

Data will be made available upon reasonable request.

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Acknowledgements

We thank Frank Geurts for help with the analyses and collecting the urine samples.

Funding

This work was funded by Stichting De Merel, The Hague, the Netherlands. The funders had no role in study design, data collection and analysis, or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Wesley J. Visser, Daan C. H. van Dorst.

Authors and Affiliations

  1. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

    Leni van Doorn, Daan C. H. van Dorst, Stijn L. W. Koolen, Esther Oomen- de Hoop, Sander Bins, Ferry A. L. M. Eskens & Ron H. J. Mathijssen

  2. Division of Dietetics, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands

    Wesley J. Visser, Anneke van Egmond- de Mik & Dominique M. Bovée

  3. Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands

    Daan C. H. van Dorst, Katrina M. Mirabito Colafella, Ingrid M. Garrelds, A. H. Jan Danser & Jorie Versmissen

  4. Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, VIC, Australia

    Katrina M. Mirabito Colafella

  5. Department of Hospital Pharmacy, Erasmus MC University Medical Center, Rotterdam, the Netherlands

    Stijn L. W. Koolen & Jorie Versmissen

  6. Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands

    Ewout J. Hoorn

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  1. Leni van Doorn
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Contributions

LvD helped design the study, included patients, helped in sample collection, performed the analyses, interpreted the results and wrote the first draft of the manuscript. WJV helped design the study, developed the sodium restricted diet and monitoring plan, helped in sample collection and analyses and reviewed the manuscript. DCHvD helped in sample collection, analyses, writing and reviewing the manuscript. KMMC and SLWK helped in analyses and reviewing the manuscript. AvE-dM helped in applying and monitoring the sodium restricted diet and reviewing the manuscript. IMG, DMB and SB helped in data acquirement, analyses and reviewing the manuscript. EO-dH helped in design of the statistical plan and helped in interpreting the results and reviewed the manuscript. FALME included helped in data acquisition, interpreting the results and writing and reviewing the manuscript. EJH helped design the study and reviewed the manuscript. AHJD and RHJM helped design the study and in interpretation of the results and helped in writing and reviewing the manuscript. JV had the original research idea, received funding, designed the study, performed the analyses and helped writing and reviewing the manuscript. All authors approved the final version and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Jorie Versmissen.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Medical Ethics Committee from the Erasmus University Medical Center (MEC-2018-155) and complies with the Declaration of Helsinki. The study was registered at the Dutch trial registry (NTR7556).

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van Doorn, L., Visser, W.J., van Dorst, D.C.H. et al. Dietary sodium restriction prevents vascular endothelial growth factor inhibitor-induced hypertension. Br J Cancer 128, 354–362 (2023). https://doi.org/10.1038/s41416-022-02036-6

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