Transcript Document

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