Nephrogenic anemia in patients receiving renal replacement therapy, pathogenesis and resistance
- Authors: Ryasnyansky V.Y.1, Shostka G.D.2, Anikonova L.I.3
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Affiliations:
- Pavlov University
- City Nephrology Center, City Mariinsky Hospital
- North-Western State Medical University named after. I.I. Mechnikov
- Issue: Vol 16, No 1 (2024)
- Pages: 58-66
- Section: Literature Reviews
- URL: https://journals.eco-vector.com/2075-3594/article/view/631135
- DOI: https://doi.org/10.18565/nephrology.2024.1.58-66
- ID: 631135
Cite item
Abstract
The sequence of involvement of factors contributed to the pathogenesis of nephrogenic anemia (NA) begins with the development of nephrosclerosis, retention of uremic toxins and activation of inflammatory cytokines; disturbances in the oxygen sensor in the kidneys, regulation of erythropoiesis, synthesis of endogenous erythropoietin and the development of its deficiency, development of functional iron deficiency and eryptosis are secondary mechanisms for the development of NA. Understanding of these processes serves as the basis for pathogenetic therapy of NA with iron preparations and recombinant human epoetin (rhEPO), which allows achieving the target hemoglobin level in 95% of patients. Transient resistance due to complications of CKD or intercurrent diseases may develop in a significant proportion of patients. What is the role of rhEPO, iron supplements, and prolyl hydroxylase inhibitors in the treatment of resistant anemia? There is no consensus on this issue. Knowledge of the characteristics of NA resistance allows to justify therapeutic tactics, minimizing the risks of using erythropoiesis-stimulating drugs.
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About the authors
Vladimir Yu. Ryasnyansky
Pavlov University
Author for correspondence.
Email: meddir@nephromed.ru
ORCID iD: 0009-0004-5886-5709
Cand.Sci. (Med.), Associate Professor at the Department of Nephrology and Dialysis
Russian Federation, St. PetersburgGeorgy D. Shostka
City Nephrology Center, City Mariinsky Hospital
Email: shostkaprof@mail.ru
Dr.Sci. (Med.), Professor
Russian Federation, St. PetersburgLyudmila I. Anikonova
North-Western State Medical University named after. I.I. Mechnikov
Email: anikonovaspb@mail.ru
ORCID iD: 0000-0003-4492-5841
Cand.Sci. (Med.), Associate Professor at the Department of Internal Diseases, Clinical Pharmacology and Nephrology
Russian Federation, St. PetersburgReferences
- Hsu C.Y., McCulloch C.E., Curhan G.C. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J. Am. Soc. Nephrol. 2002;13(2):504–10.
- Sofue T., Nakagawa N., Kanda E., et al. Prevalence of anemia in patients with chronic kidney disease in Japan: A nationwide, cross-sectional cohort study using data from the Japan Chronic Kidney Disease Database (J-CKD-DB). PLoS One. 2020;15(7):e0236132.
- Vestergaard S.V., Heide-Jørgensen U., van Haalen H., et al. Risk of Anemia in Patients with Newly Identified Chronic Kidney Disease – A Population-Based Cohort Study. Clin. Epidemiol. 2020;12:953–62.
- Yokoro M., Nakayama Y., Yamagishi S.I., et al. Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia. J. Am. Soc. Nephrol. 2017;28(9):2670–80.
- Hamza E., Metzinger L., Metzinger-Le Meuth V. Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review. Cells. 2020;9(9):2039.
- Vanholder R., Pletinck A., Schepers E., et al. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update. Toxins (Basel). 2018;10(1):33.
- Hamza E., Vallejo-Mudarra M., Ouled-Haddou H., et al. Indoxyl sulfate impairs erythropoiesis at BFU-E stage in chronic kidney disease. Cell. Signal. 2023;104:110583. Hamza E, Metzinger L, Metzinger-Le Meuth V. Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review. Cells. 2020 Sep 6;9(9):2039.
- Babitt J.L., Sitara D. Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease. Curr. Opin. Nephrol. Hypertens. 2019;28(4):304–10.
- Kim H., Yun H.R., Park S., et al. High serum adiponectin is associated with anemia development in chronic kidney disease: The results from the KNOW-CKD study. Cytokine. 2018;103:1–9.
- Chiloff D.M., de Almeida D.C., Dalboni M.A., et al. Soluble Fas affects erythropoiesis in vitro and acts as a potential predictor of erythropoiesis-stimulating agent therapy in patients with chronic kidney disease. Am. J. Physiol. Renal Physiol. 2020;318(4):F861–69.
- Tanaka M., Komaba H., Fukagawa M. Emerging Association Between Parathyroid Hormone and Anemia in Hemodialysis Patients. Ther. Apher. Dial. 2018;22(3):242–45.
- Chávez-Mendoza C.A., Martínez-Rueda A.J., Ortega-Vargas J.L., et al. Anemia, overhydration, and lower muscle strength in hemodialysis patients with protein-energy wasting. Hemodial. Int. 2022.
- Sun Y., Johnson C., Zhou J., et al. Uremic toxins are conditional danger- or homeostasis-associated molecular patterns. Front. Biosci. (Landmark Ed). 2018;23(2):348–87.
- Gusev E., Solomatina L., Zhuravleva Y., et al. The Pathogenesis of End-Stage Renal Disease from the Standpoint of the Theory of General Pathological Processes of Inflammation. Int. J. Mol. Sci. 2021;22:11453.
- Orkin S.H. Diversification of haematopoietic stem cells to specific lineages. Nat. Rev. Genet. 2000;1(1):57–64.
- Raza Y., Salman H., Luberto C. Sphingolipids in Hematopoiesis: Exploring Their Role in Lineage Commitment. Cells. 2021;10(10):2507.
- Orsini M., Chateauvieux S., Rhim J., et al. Sphingolipid-mediated inflammatory signaling leading to autophagy inhibition converts erythropoiesis to myelopoiesis in human hematopoietic stem/progenitor cells. Cell. Death Differ. 2019;26(9):1796–812.
- Morales-Mantilla D.E., King K.Y. The Role of Interferon-Gamma in Hematopoietic Stem Cell Development, Homeostasis, and Disease. Curr. Stem. Cell. Rep. 2018;4(3):264–71.
- Libregts S.F., Gutiérrez L., de Bruin A.M., et al. Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood. 2011;118(9):2578–88.
- McCranor B.J., Kim M.J., Cruz N.M., et al. Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cell. Mol. Dis. 2014;52(2–3):126–33.
- Richard C., Verdier F. Transferrin Receptors in Erythropoiesis. Int. J. Mol. Sci. 2020;21(24):9713.
- Khalil S., Delehanty L., Grado S., et al. Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor. J. Exp. Med. 2018;215(2):661–79.
- Morris R., Zhang Y., Ellyard J.I., et al. Structural and functional analysis of target recognition by the lymphocyte adaptor protein LNK. Nat. Commun. 2021;12(1):6110.
- Bhoopalan S.V., Huang L.Js., Weiss M.J. Erythropoietin regulation of red blood cell production: from bench to bedside and back [version 1; peer review: 4 approved]. F1000 Res. 2020;9(Faculty Rev.):1153.
- Araki D., Alvarado L.J., Huntsman H.D., et al. IFN-γ directly inhibits the activity of erythropoietin in human erythroid progenitors. Blood Cell. Mol. Dis. 2020;85:102488.
- Lévesque J.P., Summers K.M., Bisht K., et al. Macrophages form erythropoietic niches and regulate iron homeostasis to adapt erythropoiesis in response to infections and inflammation. Exp. Hematol. 2021;103:1–14.
- Sebastiani G., Wilkinson N., Pantopoulos K. Pharmacological Targeting of the Hepcidin/Ferroportin Axis. Front. Pharmacol. 2016;7:160.
- Souma T., Yamazaki S., Moriguchi T., et al. Plasticity of renal erythropoietin-producing cells governs fibrosis. J. Am. Soc. Nephrol. 2013;24(10):1599–616.
- Shih H.M., Pan S.Y., Wu C.J., et al. Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells. J. Biomed. Sci. 2021;28(1):73.
- La Ferla K., Reimann C., Jelkmann W., et al. Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J. 2002;16(13):1811–13.
- Batmunkh C., Krajewski J., Jelkmann W., et al. Erythropoietin production: Molecular mechanisms of the antagonistic actions of cyclic adenosine monophosphate and interleukin-1. FEBS Lett. 2006;580(13):3153–60.
- Chang Y.T., Yang C.C., Pan S.Y., et al. DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys. J. Clin. Invest. 2016;126(2):721–31.
- La Ferla K., Reimann C., Jelkmann W., et al. Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J. 2002;16(13):1811–13.
- Rivkin M., Simerzin A., Zorde-Khvalevsky E., et al. Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-Derived Erythropoietin and Anemia. Gastroenterol. 2016;151(5):999–1010.e3.
- Chou Y.H., Pan S.Y., Shao Y.H., et al. Methylation in pericytes after acute. injury promotes chronic kidney disease. J. Clin. Invest. 20201;130(9):4845–57.
- LeBleu V.S., Taduri G., O'Connell J., et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 2013;19(8):1047–53.
- Di X., Chen J., Li Y., et al. Crosstalk between fibroblasts and immunocytes in fibrosis: From molecular mechanisms to clinical trials. Clin. Transl. Med. 2024;14(1):e1545.
- Sato K., Hirano I., Sekine H., et al. An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts. Sci. Rep. 2019;9(1):11254.
- Clementi A., Virzi G.M., Milan Manani S., et al. Eryptosis in Patients with Chronic Kidney Disease: A Possible Relationship with Oxidative Stress and Inflammatory Markers. J. Clin. Med. 2022;11:7167.
- Alghareeb S.A., Alfhili M.A., Fatima S. Molecular Mechanisms and Pathophysiological Significance of Eryptosis. Int. J. Mol. Sci. 2023;24(6):5079.
- Rostoker G., Dekeyser M., Francisco S., et al. Relationship between bone marrow iron load and liver iron concentration in dialysis-associated haemosiderosis. EBioMedicine. 2024;99:104929.
- Hatamizadeh P., Ravel V., Lukowsky L.R., et al. Iron indices and survival in maintenance hemodialysis patients with and without polycystic kidney disease. Nephrol. Dial. Transplant. 2013;28(11):2889–98.
- Kuo K.L., Liu J.S., Lin M.H., et al. Taiwan Society of Nephrology Renal Registry Data System Research Group. Association of anemia and iron parameters with mortality among prevalent peritoneal dialysis patients in Taiwan: the AIM-PD study. Sci. Rep. 2022;12(1):1269.
- Zitt E., Sturm G., Kronenberg F., et al. Iron supplementation and mortality in incident dialysis patients: an observational study. PLoS One. 2014;9(12):e114144.
- Rostoker G., Vaziri N.D., Fishbane S. Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century. Drugs. 2016;76(7):741–57.
- Рябов С.И., Шостка Г.Д., Эритрон и почка. Л., 1985. 222 с. [Ryabov S.I., Shostka G.D., Erythron and kidney. L., 1985. 222 p. (In Russ.).
- Shaw A.B. Haemolysis in chronic renal failure. Br. Med. J. 1967;2(5546): 213–16.
- Eschbach J.W., Adamson J.W. Anemia of end-stage renal disease (ESRD). Kidney Int. 1985;28(1):1–5.
- Yang X., Zhao B., Wang J., et al. Red blood cell lifespan in long-term hemodialysis patients treated with roxadustat or recombinant human erythropoietin. Ren. Fail. 2021;43(1):1428–36.
- Vos F.E., Schollum J.B., Coulter C.V., et al. Red blood cell survival in long-term dialysis patients. Am. J. Kidney Dis. 2011;58(4):591–8.
- Sato Y., Mizuguchi T., Shigenaga S., et al. Shortened red blood cell lifespan is related to the dose of erythropoiesis-stimulating agents requirement in patients on hemodialysis. Ther. Apher. Dial. 2012;16(6):522–28.
- Souma T., Nezu M., Nakano D., et al. Erythropoietin synthesis in renal myo fi broblasts is restored by activation of hypoxia signaling. JASN. 2016;27:428–38.
- Lönnberg M., Garle M., Lönnberg L., et al. Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis. J. Pharm. Biomed. Anal. 2013;81–82:187–92.
- Yanagawa T., Hirayama A., Osada K., et al. Sufficient liver erythropoietin synthesis is induced in hemodialysis patients not requiring erythropoiesis-stimulating agents. Clin. Nephrol. 2022;98(3):167–70.
- Анемия при хронической болезни почек. Клинические рекомендации. МЗ, 2020. 36 с. [Anemia in chronic kidney disease. Clinical recommendations. MOH, 2020. 36 p. (In Russ.)].
- Johnson D.W., Pollock C.A., Macdougall I.C. Erythropoiesis-stimulating agent hyporesponsiveness. Nephrol. (Carlton). 2007;12(4):321–30.
- Gilbertson D.T., Peng Y., Arneson T.J., et al. Comparison of methodologies to define hemodialysis patients hyporesponsive to epoetin and impact on counts and characteristics. BMC. Nephrol. 2013;14:44.
- Eschbach J.W., Abdulhadi M.H., Browne J.K., et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann. Intern. Med. 1989;111(12):992–1000.
- Zaoui P., Courivaud C., Rostoker G., et al. Management of anaemia in French dialysis patients: results from a large epidemiological retrospective study. Clin. Kidney J. 2022;16(3):501–11.
- Shah H.H., Uppal N.N., Fishbane S. Inflammation and Erythropoiesis-Stimulating Agent Hyporesponsiveness: A Critical Connection. Kidney Med. 2020;2(3):245–47.
- Sibbel S.P., Koro C.E., Brunelli S.M., et al. Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients. BMC. Nephrol. 2015;16:144.
- Goodkin D.A., Zhao J., Cases A., et al. Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient. Am. J. Nephrol. 2022;53(5):333–42.
- Goodkin D.A., Zhao J., Cases A., et al. Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient. Am. J. Nephrol. 2022;53(5):333–42.
- Aspinall S.L., Cunningham F.E., Zhao X., et al. ESA Clinic Study Group. Impact of pharmacist-managed erythropoiesis-stimulating agents clinics for patients with non-dialysis- pendent CKD. Am. J. Kidney Dis. 2012;60(3): 371–79.
- Zheng Q., Zhang P., Yang H., et al. Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors versus erythropoiesis-stimulating agents on iron metabolism and inflammation in patients undergoing dialysis: A systematic review and meta-analysis. Heliyon. 2023;9(4):e15310.
- Li J., Haase V.H., Hao C.M. Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia. Kidney Dis. (Basel). 2022;9(1):1–11.
- Zhou Y., Chen X.X., Zhang Y.F., et al. Roxadustat for dialysis patients with erythropoietin hypo-responsiveness: a single-center, prospective investigation. Intern. Emerg. Med. 2021;16(8):2193–99.
- Wang X., Cai H., Xu H., et al. Efficacy of roxadustat in maintenance hemodialysis patients with erythropoietin-hyporesponsive anemia. Clin. Nephrol. 2024;101(1):25–33.
- Chong S., Xie Q., Ma T., et al. Risk of infection in roxadustat treatment for anemia in patients with chronic kidney disease: A *systematic review with meta-analysis and trial sequential analysis. Front. Pharmacol. 2022;13:967532.
- Chen D., Niu Y., Liu F., et al. Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis. Front. Pharmacol. 2023;14:1163908.
- Назаров В.Д., Лапин С.В., Добронравов В.А. и др. Циркулирующие антитела к эритропоэтину связаны со снижением эффективности лечения анемии рекомбинатнымим эритропоэтинами у пациентов на гемодиализе. Медицинская иммунология. 2018;20(1):129–34. [Nazarov V.D., Lapin S.V., Dobronravov V.A., et al. Circulating antibodies to erythropoietin are associated with lower efficacy of recombinant epoetin treatment in patients undergoing haemodialysis. Medical Immunology (Russia). 2018;20(1):129–134. (In Russ.) https://doi.org/10.15789/1563-0625-2018-1-129-134
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