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