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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 Normal values in adults RBC parameter Men Women Hb (g/dL) 15.7±1.7 13.8±1.5 Haematocrit (%) 46.0±4.0 40.0±4.0 RBC count (x1012/L) 5.2±0.7 4.6±0.5 Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15 The Role of Erythropoietin in Erythropoiesis Stage 1: CD-34 Stem cell pool Progenitor cells BFU-E, CFU-E Stage 2: Erythron Precursor cells erythroblasts Mature cells GM-CSF IL-3, IGF-1 SCF Erythropoietin Erslev & Besarab. Kidney Int. 1997;51:622-630 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 Erythropoietin : from kidney to bone marrow 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 EPO Membrane P JAK2 P STAT P JAK2 P STAT P P Target genes Regulation of Erythropoiesis Feedback loop Erythroid marrow Erythropoietin RBCs Kidney Circulating RBCs O2 Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441 Hb and Erythropoietin: the Non-Anaemic Patient O2 Hb transport capacity peripheral hypoxia kidney peritubular cells serum EPO precursor cells O2 transport capacity Hb EPO=erythropoietin erythroblasts erythrocytes reticulocytes Regulation of Erythropoietin Production Normoxia HIF-1 oxidation OH Proteosomal degradation HIF=hypoxia-inducible factor HIF-1 Regulation of Erythropoietin Production Hypoxia HIF-1 oxidation HIF-1 HIF-1 HIF-1 OH Proteosomal degradation EPO gene Serum EPO mRNA Breakdown of Mature RBCs Extravascular destruction: phagocytic action of fixed macrophages in the liver, spleen, and lymph nodes Intravascular destruction: hemolyse in circulation 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 The Lifecycle of the RBC 120 days Globin Circulation Amino acids Erythropoiesis in bone marrow Fe3+ Transferrin Fe Heme Ferritin and haemosiderin Biliverdin Bilirubin Macrophage in spleen, liver or red bone marrow Bilirubin Liver EXCRETION Defining Anemia Guideline Definition of Anemia European Best Practice Guidelines (EBPG) 2004 Anemia Guideline <12.0 g/d: in males and postmenopausal females; <11.0 g/dL in premenopausal females and prepubertal patients Kidney Disease Outcomes Quality Initiative (KDOQI) 2006 Anemia Guideline <13.5 g/dL males <12.0 g/dL females Causes of Anemia Gender, Age, Race Serious Illness Malnutrition/ Poverty Chronic Kidney Disease What is Chronic Kidney Disease (CKD) ? Anatomy of the Kidney Nephron Network Filtration Reabsorption Secretion Definition of Chronic 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 Symptoms of CKD CKD: Regulation of Erythropoiesis Disrupted feedback loop Erythroid marrow Erythropoietin RBCs Kidney Circulating RBCs O2 Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441 Hb and Erythropoietin: the Anaemic Patient with CKD O2 Hb transport capacity peripheral hypoxia kidney peritubular cells DAMAGED serum EPO precursor cells O2 transport capacity erythroblasts ANAEMIA Hb erythrocytes reticulocytes INSUFFICIENT Defining Renal Anaemia Erythropoietin levels in patients with non-renal and renal anaemia Serum EPO (mU/mL) 100 000 Bilateral nephrectomy 10 000 CKD Non-renal anaemia 1000 100 10 1 0 10 20 30 40 50 60 70 Haematocrit, % Adapted from Caro et al. J Lab Clin Med. 1979;93:449-458 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 Kidney Diseases Glomerulonephritis Polycystic Kidney Disease Hypertension and CKD Diabetes and CKD Diabetes and Anaemia Nephropathy (35%) CKD Neuropathy (50%) ↓Serum EPO level Diabetes Anaemia Hyperglycaemia ↓Serum EPO response RBC abnormalities ↓ RBC survival Anaemia in CKD Manifestations Anaemia in CKD induces – increased cardiovascular (CV) workload leading to left ventricular hypertrophy (LVH) – reduced exercise capacity – fatigue Anaemia in CKD is linked with – increased CV morbidity and mortality Reciprocal Relationships: Diabetes, CKD, CVD, and Anaemia CKD Diabetes Anaemia CVD CVD=cardiovascular disease CKD and Anaemia Increase the Risk of CHF Stage 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 The Cardio-Renal Anaemia Syndrome A vicious circle Hypoxia CKD Anaemia Serum EPO production Apoptosis Renal vasoconstriction Fluid retention Cardiac output Hypoxia Sympathetic activity TNF-α Uraemia CHF CHF=congestive heart failure Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47 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