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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.

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red blood cell rbc production
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

the role of erythropoietin in erythropoiesis

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

the role of erythropoietin in erythropoiesis1
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 receptor

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
regulation of erythropoiesis feedback loop
Regulation of ErythropoiesisFeedback loop

Erythroid marrow

CirculatingRBCs

RBCs

Kidney

O2

Erythropoietin

Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

hb and erythropoietin the non anaemic patient
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

regulation of erythropoietin production normoxia
Regulation of Erythropoietin ProductionNormoxia

HIF-1

HIF-1

oxidation

OH

Proteosomal degradation

HIF=hypoxia-inducible factor

regulation of erythropoietin production hypoxia
Regulation of Erythropoietin ProductionHypoxia

HIF-1

HIF-1

HIF-1

oxidation

HIF-1

OH

Proteosomal degradation

EPO gene

SerumEPO

mRNA

breakdown of mature rbcs
Extravascular destruction:phagocytic action of fixed macrophages in the liver, spleen, and lymph nodesBreakdown of Mature RBCs

Intravascular destruction:hemolyse in circulation

the role of erythropoietin in neocytolysis
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

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
causes of anemia
Causes of Anemia
  • Gender, Age, Race
  • Serious Illness
  • Malnutrition/ Poverty
  • Chronic Kidney Disease
nephron network
Nephron Network
  • Filtration
  • Reabsorption
  • Secretion
definition of chronic kidney disease ckd
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

ckd regulation of erythropoiesis disrupted feedback loop
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

hb and erythropoietin the anaemic patient with ckd
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

defining renal anaemia erythropoietin levels in patients with non renal and renal anaemia

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

erythropoietin and the pathophysiology of renal anaemia
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
Kidney Diseases

Glomerulonephritis

Polycystic Kidney Disease

diabetes and anaemia
DiabetesDiabetes and Anaemia

Nephropathy (35%)

CKD

↓Serum EPO level

Neuropathy (50%)

Anaemia

↓Serum EPO response

Hyperglycaemia

↓RBC survival

RBC abnormalities

anaemia in ckd manifestations
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
reciprocal relationships diabetes ckd cvd and anaemia
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
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

the cardio renal anaemia syndrome a vicious circle
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

anaemia in ckd summary
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