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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
RBC parameterNormal values in adults
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
Erslev & Besarab. Kidney Int. 1997;51:622-630
GM-CSFIL-3, IGF-1SCF
Erythropoietin
Stage 1: CD-34 Stage 2: Erythron
Stem cell pool
Progenitor cellsBFU-E, CFU-E
Mature cellsPrecursor cellserythroblasts
The Role of Erythropoietin in Erythropoiesis
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
Membrane
JAK2P JAK2 P
P
P
P
P
EPO
Target genes
STAT
STAT
Regulation of ErythropoiesisFeedback loop
Erythropoietin
RBCsErythroid marrow
CirculatingRBCs
Kidney
Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441
O2
Hb O2transportcapacity
peripheral hypoxia
kidneyperitubular cells
serum EPO
precursor cells
erythroblasts
reticulocytes erythrocytesHb
O2transportcapacity
Hb and Erythropoietin: the Non-Anaemic Patient
EPO=erythropoietin
Regulation of Erythropoietin ProductionNormoxia
HIF=hypoxia-inducible factor
oxidationHIF-1
OH
HIF-1
Proteosomal degradation
oxidation
Regulation of Erythropoietin ProductionHypoxia
HIF-1
HIF-1
EPO gene
mRNASerumEPO
HIF-1
OH
HIF-1
Proteosomal degradation
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;349:1389-1390Rice et al. Am J Kidney Dis. 1999;33:59-62
The Lifecycle of the RBC
EXCRETIONMacrophage in spleen, liver or red bone marrow
Globin
Amino acids
Heme
Biliverdin
Bilirubin
Fe
Bilirubin
Circulation120 days
Fe3+ Transferrin
Ferritin and haemosiderin
Liver
Erythropoiesis in bone marrow
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 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
Symptoms of CKD
Erythropoietin
RBCsErythroid marrow
CirculatingRBCs
Kidney O2
CKD: Regulation of ErythropoiesisDisrupted feedback loop
Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441
Hb O2transportcapacity
peripheral hypoxia
kidneyperitubular cells
serum EPO
precursor cells
erythroblasts
reticulocytes erythrocytesHb
O2transportcapacity
Hb and Erythropoietin: the Anaemic Patient with CKD
DAMAGED
INSUFFICIENT
ANAEMIA
Adapted from Caro et al. J Lab Clin Med. 1979;93:449-458
Defining Renal Anaemia Erythropoietin levels in patients with non-renal and renal anaemia
Bilateral nephrectomy
Non-renal anaemia
CKD
100 000
10 000
1000
100
10
1
Serum EPO (mU/mL)
0 10 20 30 40 50 60 70
Haematocrit, %
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
Diabetes
Hyperglycaemia ↓Serum EPO response
RBC abnormalities ↓ RBC survival
Anaemia
Nephropathy (35%) CKD
Neuropathy (50%) ↓Serum EPO level
Anaemia in CKDManifestations
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
Anaemia
CKD
CVD
Diabetes
CVD=cardiovascular disease
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;47:186-1922. Foley et al. Am J Kidney Dis. 1996;28:53-61
The Cardio-Renal Anaemia SyndromeA vicious circle
Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47
CKD Anaemia
Hypoxia
Sympathetic activity
TNF-α
Renal vasoconstriction
Uraemia
Fluid retention
Serum EPO production Apoptosis
Hypoxia
Cardiacoutput
CHF=congestive heart failure
CHF
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