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Erythropoiesis and the Pathophysiology of Anaemia in CKD

Erythropoiesis and the Pathophysiology of Anaemia in CKD. Anatomy of a Red Blood Cell. Function of a Red Blood Cell. Hemoglobin and Hematocrit. Red Blood Cell (RBC) Production. 2 000 000 cells/sec 120 000 000 cells/min 173 000 000 000 cells/day.

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Erythropoiesis and the Pathophysiology of Anaemia in CKD

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  1. Erythropoiesis and the Pathophysiology of Anaemia in CKD

  2. Anatomy of a Red Blood Cell

  3. Function of a Red Blood Cell

  4. Hemoglobin and Hematocrit

  5. Red Blood Cell (RBC) Production • 2 000 000 cells/sec • 120 000 000 cells/min • 173 000 000 000 cells/day Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15

  6. Stage 1: CD-34 Stage 2: Erythron Mature cells Stem cell pool Progenitor cells BFU-E, CFU-E Precursor cells erythroblasts The Role of Erythropoietin in Erythropoiesis GM-CSF IL-3, IGF-1 SCF Erythropoietin Erslev & Besarab. Kidney Int. 1997;51:622-630

  7. The Role of Erythropoietin in Erythropoiesis • Erythropoietin ensures the maturation of progenitor cells into RBCs • Erythropoietin rescues neocytes from apoptosis • Erythropoietin helps to sustain RBC proliferation and differentiation

  8. Erythropoietin : from kidney to bone marrow

  9. EPO Membrane P P JAK2 JAK2 STAT P P STAT P P Target genes Erythropoietin Receptor • 508 amino acids, 66–78 kDa glycoprotein • Located on erythroid progenitor cell surface • Approximately 1000 erythropoietin receptors per cell • Expression • primarily on CFU-E • small numbers on BFU-E • no receptors present once cells become reticulocytes

  10. Regulation of ErythropoiesisFeedback loop Erythroid marrow CirculatingRBCs RBCs Kidney O2 Erythropoietin Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

  11. Hb and Erythropoietin: the Non-Anaemic Patient O kidney 2 peripheral Hb peritubular transport hypoxia cells capacity serum EPO O precursor cells 2 transport capacity erythroblasts reticulocytes Hb erythrocytes EPO=erythropoietin

  12. Regulation of Erythropoietin ProductionNormoxia HIF-1 HIF-1 oxidation OH Proteosomal degradation HIF=hypoxia-inducible factor

  13. Regulation of Erythropoietin ProductionHypoxia HIF-1 HIF-1 HIF-1 oxidation HIF-1 OH Proteosomal degradation EPO gene SerumEPO mRNA

  14. Extravascular destruction:phagocytic action of fixed macrophages in the liver, spleen, and lymph nodes Breakdown of Mature RBCs Intravascular destruction:hemolyse in circulation

  15. The Role of Erythropoietin in Neocytolysis • Selective haemolysis of young RBCs • Thought to be precipitated by erythropoietin suppression • May permit rapid adaptation to a new environment • down-regulation of ‘excessive’ RBC mass • Observed primarily in studies of astronauts and individuals descending from altitude • May contribute to anaemia in patients with diminished erythropoietin levels Alfrey et al. Lancet. 1997;349:1389-1390 Rice et al. Am J Kidney Dis. 1999;33:59-62

  16. 120 days Circulation Amino acids Erythropoiesis in bone marrow Globin Fe3+ Transferrin Fe Heme Ferritin and haemosiderin Biliverdin Bilirubin Bilirubin Liver Macrophage in spleen, liver or red bone marrow EXCRETION The Lifecycle of the RBC

  17. Defining Anemia

  18. Causes of Anemia • Gender, Age, Race • Serious Illness • Malnutrition/ Poverty • Chronic Kidney Disease

  19. What is Chronic Kidney Disease(CKD) ?

  20. Anatomy of the Kidney

  21. Nephron Network • Filtration • Reabsorption • Secretion

  22. Definition ofChronic Kidney Disease (CKD) • CKD in early stages is characterised by kidney damage and level of kidney function • CKD in later stages is defined as an estimated glomerular filtration rate (eGFR) for at least 3 months of • eGFR <60 mL/min/1.73m2 • Stages of CKD are ranked by classifying severity of disease with declining eGFR and kidney damage NKF K/DOQI Clinical Practice Guidelines 2002: Am J Kidney Dis 2002; 39 (2 Suppl 1): S17-S31

  23. Symptoms of CKD

  24. CKD: Regulation of ErythropoiesisDisrupted feedback loop Erythroid marrow CirculatingRBCs RBCs Kidney O2 Erythropoietin Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

  25. Hb and Erythropoietin: the Anaemic Patient with CKD O kidney 2 peripheral Hb peritubular transport hypoxia cells capacity DAMAGED serum EPO O precursor cells 2 transport capacity erythroblasts ANAEMIA reticulocytes Hb erythrocytes INSUFFICIENT

  26. Serum EPO (mU/mL) 100 000 Bilateral nephrectomy 10 000 CKD 1000 Non-renal anaemia 100 10 1 0 10 20 30 40 50 60 70 Haematocrit, % Defining Renal AnaemiaErythropoietin levels in patients with non-renal and renal anaemia Adapted from Caro et al. J Lab Clin Med. 1979;93:449-458

  27. Erythropoietin and the Pathophysiology of Renal anaemia • Renal disease in progressive renal failure is almost always accompanied by a normochromic, normocytic anaemia† • Severity of anaemia correlates with severity of kidney disease • Anaemia associated with kidney disease results from multiple factors • failure of the erythropoietin response as a result of kidney damage • significant reduction in circulating RBC lifespan secondary to uraemia • reduced bone marrow response to circulating erythropoietin †anaemia characterised by RBCs which are normal in morphology and Hb content, but are too few to sustain adequate oxygen transport

  28. Kidney Diseases Glomerulonephritis Polycystic Kidney Disease

  29. Hypertension and CKD

  30. Diabetes and CKD

  31. Diabetes Diabetes and Anaemia Nephropathy (35%) CKD ↓Serum EPO level Neuropathy (50%) Anaemia ↓Serum EPO response Hyperglycaemia ↓RBC survival RBC abnormalities

  32. Anaemia in CKDManifestations • Anaemia in CKD induces • increased cardiovascular (CV) workload leading toleft ventricular hypertrophy (LVH) • reduced exercise capacity • fatigue • Anaemia in CKD is linked with • increased CV morbidity and mortality

  33. Reciprocal Relationships: Diabetes, CKD, CVD, and Anaemia CKD Diabetes Anaemia CVD CVD=cardiovascular disease

  34. CKD and Anaemia Increase the Risk of CHFStage 5 CKD patients on dialysis (n=433) • At start of dialysis • 31% had CHF • 19% had angina • 14% had coronary artery disease • On dialysis, for each 1 g/dL fall in Hb • 42% increased risk of LVH • 18% increased risk of CHF • 14% increased risk of death 1. Foley et al. Kidney Int. 1995;47:186-192 2. Foley et al. Am J Kidney Dis. 1996;28:53-61

  35. The Cardio-Renal Anaemia SyndromeA vicious circle Hypoxia CKD Anaemia Serum EPO production Apoptosis Cardiacoutput Fluid retention Renal vasoconstriction Uraemia Sympathetic activity TNF-α Hypoxia CHF Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47 CHF=congestive heart failure

  36. Anaemia in CKD: Summary • The hormone erythropoietin is the physiological regulator of RBC production and lifespan • In individuals with CKD, damage to the kidney compromises erythropoietin production • Anaemia correlates with the severity of CKD • Strong inter-relationships exist between CKD, anaemia, and CVD

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