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Suicidal erythrocyte death in end-stage renal disease

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Abstract

Anemia in end-stage renal disease (ESRD) results mainly from erythropoietin and iron deficiency. Anemia could be confounded, however, by accelerated clearance of circulating erythrocytes because of premature suicidal erythrocyte death or eryptosis characterized by phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increased cytosolic Ca2+ concentration ([Ca2+]i), oxidative stress, and ceramide. The present study explored whether and how ESRD influences eryptosis. Blood was drawn from healthy volunteers (n = 20) as well as ESRD patients (n = 20) prior to and after hemodialysis. Phosphatidylserine exposure was estimated from annexin V binding, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) from 2′,7′dichlorodihydrofluorescein fluorescence, and ceramide from fluorescein-isothiocyanate-conjugated antibody binding in flow cytometry. Measurements were made in erythrocytes from freshly drawn blood and in erythrocytes from healthy volunteers exposed in vitro for 24 h to plasma from healthy volunteers or ESRD patients prior to and following dialysis. The patients suffered from anemia (hemoglobin 10.1 ± 0.5 g/100 ml) despite 1.96 ± 0.34 % reticulocytes. The percentage of phosphatidylserine-exposing erythrocytes was significantly higher in ESRD patients (0.84 ± 0.09 %) than in healthy volunteers (0.43 ± 0.04 %) and was significantly increased immediately after dialysis (1.35 ± 0.13 %). The increase in phosphatidylserine exposure was paralleled by increase in [Ca2+]i, oxidative stress, and ceramide abundance. As compared to addition of plasma from healthy individuals, addition of predialytic but not of postdialytic plasma from ESRD patients increased phosphatidylserine exposure, [Ca2+]i, ROS, and ceramide abundance. In conclusion, both, dialyzable components of uremic plasma and dialysis procedure, trigger eryptosis at least in part by increasing erythrocyte [Ca2+]i, ROS, and ceramide formation.

Key Messages

  • Anemia in uremia results in part from eryptosis, the suicidal erythrocyte death.

  • Eryptosis in uremia is triggered in part by a dialyzable plasma component.

  • Eryptosis in uremia is further triggered by dialysis procedure.

  • Eryptosis in uremia is in part due to increased cytosolic Ca2+ concentration.

  • Eryptosis in uremia is further due to oxidative stress and ceramide formation.

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Acknowledgments

The study was supported by the Deutsche Forschungsgemeinschaft.

Disclosure

All authors of this manuscript declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Physiology, University of Tuebingen, Gmelinstrasse 5, Tübingen, Germany

    Majed Abed, Kousi Alzoubi, Sabina Honisch, Michael Föller & Florian Lang

  2. Department of Internal Medicine, Section of Nephrology, University of Tuebingen, Otfried-Müller-Straße 10, 72076, Tuebingen, Germany

    Ferruh Artunc & Dorothea Baumann

  3. Physiologisches Institut, der Universität Tübingen, Gmelinstr. 5, D-72076, Tübingen, Germany

    Florian Lang

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  1. Majed Abed
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  2. Ferruh Artunc
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Correspondence to Florian Lang.

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Abed, M., Artunc, F., Alzoubi, K. et al. Suicidal erythrocyte death in end-stage renal disease. J Mol Med 92, 871–879 (2014). https://doi.org/10.1007/s00109-014-1151-4

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  • DOI: https://doi.org/10.1007/s00109-014-1151-4

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