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Alterations in Erythrocyte Deformability and Functions Associated with End-Stage Renal Disease

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract—

End-stage renal disease (ESRD) is associated with a variety of erythron alterations including structural and functional changes in circulating erythrocytes (RBCs), which are potential risk factors to cause RBC malfunctions and corresponding anemia of different severity. However, the mechanisms of such changes in RBCs remain understudied. Here we used flow cytometry to estimate intracellular esterase activity, phosphatidylserine externalization, and reticulocyte count and state, laser diffraction for osmotic and ammonium stress tests, and spectrophotometry to evaluate the generation of unstable hemoglobin (Hb) forms in RBCs of patients with ESRD before and after the hemodialysis (HD) session. RBCs in ESRD were more osmotically fragile and had an increased swelling rate in the ammonium stress test. HD did not affect RBC deformability but led to Hb oxidation to ferryl forms and triggered such apoptosis-like events, as a decrease in intracellular esterase activity and an increase in the number of annexin-V-positive cells. Our data indicate that uremic syndrome, combined with the mechanical and chemical effects of HD therapy, challenges the erythron of HD patients and contributes to a multifactorial decrease in RBC function and aggravation of renal anemia.

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REFERENCES

  1. Glassock R.J. 2008. Uremic toxins: What are they? An integrated overview of pathobiology and classification. J. Ren. Nutr. 18 (1), 2–6.

    Article  PubMed  Google Scholar 

  2. Vos F.E., Schollum J.B., Coulter C.V., Doyle T.C., Duffull S.B., Walker R.J. 2011. Red blood cell survival in long-term dialysis patients. Am. J. Kidney Dis. 58 (4), 591–598.

    Article  PubMed  Google Scholar 

  3. Kliche K., Gerth U., Pavenstädt H., Oberleithner H. 2015. Recharging red blood cell surface by hemodialysis. Cell Physiol. Biochem. 35 (3), 1107–1115.

    Article  CAS  PubMed  Google Scholar 

  4. Bonan N.B., Steiner T.M., Kuntsevich V., Virzì G.M., Azevedo M., Nakao L.S., Barreto F.C., Ronco C., Thijssen S., Kotanko P., Pecoits-Filho R., Moreno-Amaral A.N. 2016. Uremic toxicity-induced eryptosis and monocyte modulation: The erythrophagocytosis as a novel pathway to renal anemia. Blood Purif. 41 (4), 317–323.

    Article  CAS  PubMed  Google Scholar 

  5. Fishbane S., Spinowitz B. 2018. Update on anemia in ESRD and earlier stages of CKD: Core curriculum 2018. Am. J. Kidney Dis. 71 (3), 423–435.

    Article  PubMed  Google Scholar 

  6. Georgatzakou H.T., Tzounakas V.L., Kriebardis A.G., Velentzas A.D., Papageorgiou E.G., Voulgaridou A.I., Kokkalis A.C., Antonelou M.H., Papassideri I.S. 2017. Pathophysiological aspects of red blood cells in endstage renal disease patients resistant to recombinant human erythropoietin therapy. Eur. J. Haematol. 98 (6), 590–600.

    Article  CAS  PubMed  Google Scholar 

  7. Tozoni S.S., Dias G.F., Bohnen G., Grobe N., PecoitsFilho R., Kotanko P., Moreno-Amaral A.N. 2019. Uremia and hypoxia independently induce eryptosis and erythrocyte redox imbalance. Cell Physiol. Biochem. 53, 794–804.

    Article  CAS  PubMed  Google Scholar 

  8. Ayala A., Muñoz M.F., Argüelles S. 2014. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid. Med. Cell Longev. 2014, 360438.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sindhu R.K., Ehdaie A., Farmand F., Dhaliwal K.K., Nguyen T., Zhan C.D., Roberts C.K., Vaziri N.D. 2005. Expression of catalase and glutathione peroxidase in renal insufficiency. Biochim. Biophys. Acta. 1743 (1–2), 86–92.

  10. Gao C., Xie R., Yu C., Ma R., Dong W., Meng H., Zhang Y., Si Y., Zhang Z., Novakovic V., Zhang Y., Kou J., Bi Y., Li B., Xie R., Gilbert G.E., Zhou J., Shi J. 2015. Thrombotic role of blood and endothelial cells in uremia through phosphatidylserine exposure and microparticle release. PLoS One. 10 (11), e0142835.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bonomini M., Sirolli V., Merciaro G., Antidormi T., Di Liberato L., Brummer U., Papponetti M., Cappelli P., Di Gregorio P., Arduini A. 2005. Red blood cells may contribute to hypercoagulability in uraemia via enhanced surface exposure of phosphatidylserine. Nephrol. Dial. Transplant. 20 (2), 361–366.

    Article  CAS  PubMed  Google Scholar 

  12. Luo J.F., Li J.H., Nie J.J., Li P.P., Zhang H.D., Ma Y.J. 2019. Effect of hemodialysis on the red blood cell life span in patients with end-stage kidney disease. Ther. Apher. Dial. 23 (4), 336–340.

    Article  CAS  PubMed  Google Scholar 

  13. Scherer A., Günther O.P., Balshaw R.F., Hollander Z., Wilson-McManus J., Ng R., McMaster W.R., McManus B.M., Keown P.A. 2013. Alteration of human blood cell transcriptome in uremia. BMC Med. Genomics. 6, 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Antonelou M.H., Kriebardis A.G., Velentzas A.D., Kokkalis A.C., Georgakopoulou S.C., Papassideri I.S. 2011. Oxidative stress-associated shape transformation and membrane proteome remodeling in erythrocytes of end stage renal disease patients on hemodialysis. J. Proteomics. 74 (11), 2441–2452.

    Article  CAS  PubMed  Google Scholar 

  15. Huisjes R., Bogdanova A., van Solinge W.W., Schiffelers R.M., Kaestner L., van Wijk R. 2018. Squeezing for life – Properties of red blood cell deformability. Front. Physiol. 9, 656.

    Article  PubMed  PubMed Central  Google Scholar 

  16. McMahon T.J. 2019. Red blood cell deformability, vasoactive mediators, and adhesion. Front. Physiol. 10, 1417.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Orbach A., Zelig O., Yedgar S., Barshtein G. 2017. Biophysical and biochemical markers of red blood cell fragility. Transfus. Med. Hemother. 44 (3), 183–187.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kikuchi Y., Koyama T., Koyama Y., Tozawa S., Arai T., Horimoto M., Kakiuchi Y. 1982. Red blood cell deformability in renal failure. Nephron. 30 (1), 8–14.

    Article  CAS  PubMed  Google Scholar 

  19. Barns S., Balanant M.A., Sauret E., Flower R., Saha S., Gu Y. 2017. Investigation of red blood cell mechanical properties using AFM indentation and coarse-grained particle method. Biomed. Eng. Online. 16 (1), 140.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bowry S.K., Gatti E. 2011. Impact of hemodialysis therapy on anemia of chronic kidney disease: The potential mechanisms. Blood Purif. 32 (3), 210–219.

    Article  PubMed  Google Scholar 

  21. Tugusheva F.A., Zubina I.M. 2009. Oxidative stress and its participation in nonimmune mechanisms of progressing chronic kidney disease. Nephrology. 13 (3), 42–48.

    Google Scholar 

  22. Dutka P. 2008. Guarding against hidden hemolysis during dialysis: An overview. Nephrol. Nurs. J. 35, 45.

    PubMed  Google Scholar 

  23. Ahmadmehrabi S., Tang W.H.W. 2018. Hemodialysisinduced cardiovascular disease. Semin. Dial. 31 (3), 258–267.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Depond M., Henry B., Buffet P., Ndour P.A. 2020. Methods to investigate the deformability of RBC during malaria. Front. Physiol. 10, 1613.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sohn M., Lee J.E., Ahn M., Park Y., Lim S. 2021. Correlation of dynamic membrane fluctuations in red blood cells with diabetes mellitus and cardiovascular risks. Sci. Rep. 11 (1), 7007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bratosin D., Estaquier J., Petit F., Arnoult D., Quatannens B., Tissier J.P., Slomianny C., Sartiaux C., Alonso C., Huart J.J., Montreuil J., Ameisen J.C. 2001. Programmed cell death in mature erythrocytes: A model for investigating death effector pathways operating in the absence of mitochondria. Cell Death. Differ. 8, 1143–1156.

    Article  CAS  PubMed  Google Scholar 

  27. Riley R.S., Ben-Ezra J.M., Goel R., Tidwell A. 2001. Reticulocytes and reticulocyte enumeration. J. Clin. Lab. Anal. 15 (5), 267–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mindukshev I.V., Sudnitsyna J.S., Skverchinskaya E.A., Andreyeva A.Yu., Dobrylko I.A., Senchenkova E.Yu., Krivchenko A.I., Gambaryan S.P. 2019. Erythrocytes’ reactions to osmotic, ammonium, and oxidative stress are inhibited under hypoxia. Biochem. (Moscow), Supp. Series A: Membr. Cell Biol. 13 (4), 352–364.

    Google Scholar 

  29. Sudnitsyna J.S., Skvertchinskaya E.A., Dobrylko I.A., Nikitina E.R., Krivchenko A.I., Gambaryan S.P., Mindukshev I.V. 2016. Human erythrocyte ammonium transport is mediated by functional interaction of ammonium (RhAG) and anion (AE1) transporters. Biochem. (Moscow), Supp. Series A: Membr. Cell Biol. 10 (4), 301–310.

    Google Scholar 

  30. Sudnitsyna J., Skverchinskaya E., Dobrylko I., Nikitina E., Gambaryan S., Mindukshev I. 2020. Microvesicle Formation induced by oxidative stress in human erythrocytes. Antioxidants (Basel). 9 (10), 929.

    Article  CAS  Google Scholar 

  31. Kanias T., Acker J.P. 2010. Mechanism of hemoglobininduced cellular injury in desiccated red blood cells. Free Radic. Biol. Med. 49 (4), 539–547.

    Article  CAS  PubMed  Google Scholar 

  32. Ly J., Marticorena R., Donnelly S. 2004. Red blood cell survival in chronic renal failure. Am. J. Kidney Dis. 44, 715–719.

    Article  PubMed  Google Scholar 

  33. Koma Y., Onishi A., Matsuoka H., Oda N., Yokota N., Matsumoto Y., Koyama M., Okada N., Nakashima N., Masuya D., Yoshimatsu H., Suzuki Y. 2013. Increased red blood cell distribution width associates with cancer stage and prognosis in patients with lung cancer. PLoS One. 8 (11), e80240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Evans E.A., Hochmuth R.M. 1976. Membrane viscoelasticity. Biophys. J. 16 (1), 1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bruce L.J., Beckmann R., Ribeiro M.L., Peters L.L., Chasis J.A., Delaunay J., Mohandas N., Anstee D.J., Tanner M.J. 2003. A band 3-based macrocomplex of integral and peripheral proteins in the RBC membrane. Blood. 101 (10), 4180–4188.

    Article  CAS  PubMed  Google Scholar 

  36. Borisov Yu.A., Sudnitsyna J.S., Vlasov L.V., Dulneva L.V., Abolmasov V.O., Mindukshev I.V., Smirnov A.V. 2020. Uremic syndrome triggers red blood cell deformability alteration in hemodialysis patients. Rossiiski Fiziologich. Zhurnal (Rus.). 106 (8), 1025–1040.

    CAS  Google Scholar 

  37. Evans B.A., Ansari A.K., Kamyszek R.W., Salvagno M., Welsby J., Fuller M., Welsby I. 2021. Modulation of red blood cell oxygen affinity with a novel allosteric modifier of hemoglobin is additive to the Bohr effect. Blood Cells Mol. Dis. 87, 102520.

    Article  CAS  PubMed  Google Scholar 

  38. Jensen F.B. 2009. The dual roles of red blood cells in tissue oxygen delivery: Oxygen carriers and regulators of local blood flow. J. Exp. Biol. 212 (Pt. 21), 3387–3393.

    Article  CAS  PubMed  Google Scholar 

  39. Chintagari N.R., Jana S., Alayas A.I. 2016. Oxidized ferric and ferryl forms of hemoglobin trigger mitochondrial dysfunction and injury in alveolar type I cells. Am. J. Respir. Cell Mol. Biol. 55, 288–298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pantaleo A., Ferru E., Pau M.C., Khadjavi A., Mandili G., Mattè A., Spano A., De Franceschi L., Pippia P., Turrini F. 2016. Band 3 erythrocyte membrane protein acts as redox stress sensor leading to its phosphorylation by p (72) Syk. Oxid. Med. Cell Longev. 2016, 6051093.

    Article  PubMed  Google Scholar 

  41. Sugie J., Intaglietta M., Sung L.A. 2018. Water transport and homeostasis as a major function of erythrocytes. Am. J. Physiol. Heart Circ. Physiol. 314 (5), H1098–H1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jani V.P., Lucas A., Jani V.P., Munoz C., Williams A.T., Ortiz D., Yalcin O., Cabrales P. 2020. Numerical model for the determination of erythrocyte mechanical properties and wall shear stress in vivo from intravital microscopy. Front. Physiol. 10, 1562

    Article  PubMed  PubMed Central  Google Scholar 

  43. Van Avondt K., Nur E., Zeerleder, S. 2019. Mechanisms of haemolysis-induced kidney injury. Nat. Rev. Nephrol. 15, 671–692.

    Article  CAS  PubMed  Google Scholar 

  44. Deltombe O., Van Biesen W., Glorieux G., Massy Z., Dhondt A., Eloot S. 2015. Exploring protein binding of uremic toxins in patients with different stages of chronic kidney disease and during hemodialysis. Toxins (Basel). 7 (10), 3933–3946.

    Article  CAS  Google Scholar 

  45. Itano H.A., Keitel H.G., Thompson D. 1956. Hyposthenuria in sickle cell anemia: A reversible renal defect. J. Clin. Invest. 35 (9), 998–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bonomini M., Pieroni L., Ronci M., Sirolli V., Urbani A. 2018. Blood cell proteomics in chronic kidney disease. Open Urology and Nephrology. 11, 28–38.

    Article  CAS  Google Scholar 

  47. Mohanty J.G., Nagababu E., Rifkind J. M. 2014. Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging. Front. Physiol. 5, 84.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Welbourn E.M., Wilson M.T., Yusof A., Metodiev M.V., Cooper C.E. 2017. The mechanism of formation, structure and physiological relevance of covalent hemoglobin attachment to the erythrocyte membrane. Free Radic. Biol. Med. 103, 95–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Oldenborg P.A., Zheleznyak A., Fang Y.F., Lagenaur C.F., Gresham H.D., Lindberg F.P. 2000. Role of CD47 as a marker of self on red blood cells. Science. 288 (5473), 2051–2054.

    Article  CAS  PubMed  Google Scholar 

  50. Sudnitsyna J.S., Gambaryan S.P., Krivchenko A.I., Mindukshev I.V. 2018. Ammonia/ammonium influx in human erythrocytes. Biol. Membrany (Rus.). 35(4), 398–402.

    Google Scholar 

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ACKNOWLEDGMENTS

The work was supported by the Russian Foundation for Basic Research (project no. 19-315-60 015 to J.S.) and by the State Assignment of Ministry of Science and Higher Education of the Russian Federation (project no. AAAA-A18-118012290371-3 to J.S., E.S., and I.M.).

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    Authors and Affiliations

    1. Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119991, Moscow, Russia

      J. S. Sudnitsyna

    2. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223, St. Petersburg, Russia

      J. S. Sudnitsyna, E. A. Skverchinskaya, T. O. Ruzhnikova, B. A. Kaljuzhnyi & I. V. Mindukshev

    3. Pavlov First St. Petersburg State Medical University, 197022, St. Petersburg, Russia

      I. M. Zubina, E. D. Suglobova, T. D. Vlasov, A. V. Smirnov, A. N. Vasiliev & Yu. A. Borisov

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    1. J. S. Sudnitsyna
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    Correspondence to J. S. Sudnitsyna.

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    The study was approved by the Ethical Committee of the 1st Pavlov St. Petersburg State Medical University (protocol no. 217 of January 17, 2020) and the Ethical Committee of Sechenov Institute of Evolutionary Physiology and Biochemistry (protocol no. 2-02 of February 2, 2021) and conducted in accordance with the Helsinki Declaration.

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    Sudnitsyna, J.S., Skverchinskaya, E.A., Zubina, I.M. et al. Alterations in Erythrocyte Deformability and Functions Associated with End-Stage Renal Disease. Biochem. Moscow Suppl. Ser. A 16, 79–90 (2022). https://doi.org/10.1134/S1990747821060118

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