Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review
Abstract
:1. Introduction
2. Uremic Toxins Are Central Players of the CKD Clinical Course
2.1. Representative Uremic Toxins: Indoxyl Sulfate and P-Cresyl Sulfate
2.2. IS Effects in Renal Anemia
2.3. Other Uremic Toxins Implicated in Erythropoiesis
3. Physiopathology of Anemia in CKD
3.1. Regulation of HIF in Kidney Disease
3.2. Impairment of IS-Induced HIF Activation
3.3. EPO and Regulation of Erythropoeisis
3.4. The Role of Iron in the Regulation of Erythropoeisis
3.5. Hepcidin and Regulation of Serum Iron Levels
4. Current Strategies of Renal Anemia Treatment
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Classification | Representative Solute | Cn | Cu | Cmax | MW (kDa) | Ref |
---|---|---|---|---|---|---|
Free water-soluble solute | Urea (g/L) Creatinine (mg/L) | <0.4 <12.0 | 2.3 ± 1.1 136.0 ± 46.0 | 4.6 240.0 | 60 113 | [32,33] |
Protein-bound solute | Indoxyl sulfate (mg/L) P-cresyl sulfate (mg/L) | 0.6 ± 5.4 0.6 ± 1.0 | 53.0 ± 91.5 20.1 ± 10.5 | 236.0 40.7 | 251 108 | [34,35] |
Middle molecule | β-2 microglobulin (mg/L) | <2.0 | 55.0 ± 7.9 | 100.0 | 11818 | [36,37] |
The Pathophysiological Role of Indoxyl Sulfate | Reference |
---|---|
Inhibition of endothelial proliferation and wound repair | [2] |
Progressive deterioration of renal function | [34,46,50,51,52,53,54] |
Induction of oxidative stress | [55] |
Increase of circulating EMPs release | [56] |
Induces TF production via the AhR pathway | [57,58] |
Development of uremic symptoms | [46,59] |
Associated with pathogenesis of atherosclerosis | [60] |
Increases mortality | [61] |
Cardiovascular disease | [54,61,62,63] |
Peripheral arterial disease | [61,64,65] |
The Pathophysiologic Roles of IS | Molecular Mechanisms | References |
---|---|---|
Impairment of erythropoiesis in a HIF dependent manner | Suppression of the EPO gene transcription during hypoxia | [43] |
Stimulates eryptosis | Extracellular Ca2+ entry with subsequent stimulation of cell shrinkage and cell membrane scrambling | [66] |
Might contribute to EPO resistance and endothelial dysfunction | IS inhibits EPO-Induced Phosphorylation of EPOR IS inhibits TSP-1 expression through suppression of the AKT phosphorylation | [67] |
Suppression of HIF activation | IS-induced AhR activation | [70] |
Increased PCA in RBCs | Due to PS exposure and RBCs-derived microparticles release | [71] |
EPO decrease | IS negatively regulates the EPO expression | [73] |
IS-induced RBCs death | Through OAT2, and NADPH oxidase activity-dependent, and a GSH-independent mechanism | [75] |
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Hamza, E.; Metzinger, L.; Metzinger-Le Meuth, V. Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review. Cells 2020, 9, 2039. https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092039
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. https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092039
Chicago/Turabian StyleHamza, Eya, Laurent Metzinger, and Valérie Metzinger-Le Meuth. 2020. "Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review" Cells 9, no. 9: 2039. https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092039