Erythropoiesis and the Pathophysiology of Anaemia in CKD

1

• Erythropoiesis and the Pathophysiology of
  Anaemia in CKD

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Anatomy of a Red Blood Cell

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Function of a Red Blood Cell

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Hemoglobin and Hematocrit

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Red Blood Cell (RBC) Production

• 2 000 000 cells/sec
• 120 000 000 cells/min
• 173 000 000 000 cells/day

RBC parameter Normal values in adults Normal values in adults
RBC parameter Men Women
Hb (g/dL) 15.71.7 13.81.5
Haematocrit () 46.04.0 40.04.0
RBC count (x1012/L) 5.20.7 4.60.5
Adapted from Williams et al. In Williams
Hematology. 5th ed. 19958-15
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The Role of Erythropoietin in Erythropoiesis
GM-CSF IL-3, IGF-1 SCF
Erythropoietin
Erslev Besarab. Kidney Int. 199751622-630
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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

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Erythropoietin from kidney to bone marrow

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Erythropoietin Receptor

• 508 amino acids, 6678 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

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Regulation of ErythropoiesisFeedback loop
Erythroid marrow
CirculatingRBCs
RBCs
Kidney
Erythropoietin
O2
Adapted from Erslev Beutler. In Williams
Hematology. 5th ed. 1995425-441
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Hb and Erythropoietin the Non-Anaemic Patient
O
kidney
2
peripheral
Hb
peritubular
transport
hypoxia
cells
capacity
serum EPO
precursor cells
O
2
transport
capacity
erythroblasts
reticulocytes
erythrocytes
Hb
EPOerythropoietin
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Regulation of Erythropoietin ProductionNormoxia
HIF-1?
HIF-1?
oxidation
OH
Proteosomal degradation
HIFhypoxia-inducible factor
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Regulation of Erythropoietin ProductionHypoxia
HIF-1?
HIF-1?
HIF-1?
oxidation
HIF-1?
OH
Proteosomal degradation
EPO gene
mRNA
SerumEPO
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Breakdown of Mature RBCs

• Extravascular destructionphagocytic action of
  fixed macrophages in the liver, spleen, and lymph
  nodes

Intravascular destructionhemolyse in circulation
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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. 19973491389-1390 Rice et
al. Am J Kidney Dis. 19993359-62
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The Lifecycle of the RBC
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Defining Anemia
Guideline Definition of Anemia
European Best Practice Guidelines (EBPG) 2004 Anemia Guideline lt12.0 g/d in males and postmenopausal females lt11.0 g/dL in premenopausal females and prepubertal patients
Kidney Disease Outcomes Quality Initiative (KDOQI) 2006 Anemia Guideline lt13.5 g/dL males lt12.0 g/dL females
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Causes of Anemia

• Gender, Age, Race
• Serious Illness
• Malnutrition/ Poverty
• Chronic Kidney Disease

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What is Chronic Kidney Disease(CKD) ?

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Anatomy of the Kidney

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Nephron Network

• Filtration
• Reabsorption
• Secretion

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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 lt60 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
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Symptoms of CKD

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CKD Regulation of ErythropoiesisDisrupted
feedback loop
Erythroid marrow
CirculatingRBCs
RBCs
Kidney
Erythropoietin
O2
Adapted from Erslev Beutler. In Williams
Hematology. 5th ed. 1995425-441
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Hb and Erythropoietin the Anaemic Patient with
CKD
O
kidney
2
peripheral
Hb
peritubular
transport
hypoxia
cells
capacity
DAMAGED
serum EPO
precursor cells
O
2
transport
capacity
erythroblasts
ANAEMIA
reticulocytes
erythrocytes
Hb
INSUFFICIENT
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Defining Renal Anaemia Erythropoietin levels in
patients with non-renal and renal anaemia
Adapted from Caro et al. J Lab Clin Med.
197993449-458
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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
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Kidney Diseases
Glomerulonephritis
Polycystic Kidney Disease

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Hypertension and CKD
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Diabetes and CKD
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Diabetes and Anaemia
Nephropathy (35)
CKD
?Serum EPO level
Neuropathy (50)

• Diabetes

Anaemia
?Serum EPO response
Hyperglycaemia
RBC abnormalities
? RBC survival
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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

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Reciprocal Relationships Diabetes, CKD, CVD, and
Anaemia
CKD
Diabetes
Anaemia
CVD
CVDcardiovascular disease
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CKD and Anaemia Increase the Risk of CHFStage 5
CKD patients on dialysis (n433)

• 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. 199547186-192 2.
Foley et al. Am J Kidney Dis. 19962853-61
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Anemia, Heart Disease and CKD
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The Cardio-Renal Anaemia SyndromeA vicious circle
Hypoxia
CKD
Anaemia
Serum EPO production Apoptosis
Cardiacoutput
Fluid retention
Sympathetic activity TNF-a
Renal vasoconstriction Uraemia
Hypoxia
CHF
Adapted from Silverberg et al. Kidney Int Suppl.
2003(87)S40-S47
CHFcongestive heart failure
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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