1. Erythropoiesis and the Pathophysiology of Anaemia in CKD1

2. Anatomy of a Red Blood Cell

3. Function of a Red Blood Cell

4. Hemoglobin and Hematocrit

5. Red Blood Cell (RBC) Production
cells/sec
cells/min
cells/day
RBC parameter
Normal 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
Erythropoiesis, the production and replenishment of red blood cells (RBCs), is a responsive and dynamic mechanism. Under normal circumstances, RBCs are produced in the bone marrow at a rate of 120 million per minute to compensate for the normal loss of RBCs from the circulation.
In the healthy individual, RBC count, and hence haemoglobin (Hb) level, is usually maintained at a constant level, although the absolute level can vary between individuals of the same gender by as much as 15%. In general, men have a higher Hb level than women due to greater production of testosterone and the absence of menstrual bleeding.
Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15
Williams WJ et al. Examination of the blood. In: Beutler E et al, eds. Williams’ Hematology, fifth edition. New York: McGraw-Hill;1995:8-15.
Macdougall I. Pocket reference to renal anaemia. Science Press 2003. 5

6. The Role of Erythropoietin in Erythropoiesis
Stage 1: CD-34
Stage 2: Erythron
Stem cell
pool
Progenitor cells
BFU-E, CFU-E
Mature cells
Precursor cells
erythroblasts
The transformation of haematopoietic stem cells into mature blood cells happens in two morphologically distinct stages, of which only the first is responsive to erythropoietin.
Erythropoietin works synergistically with various regulatory factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), insulin-like growth factor-1 (IGF-1), and stem cell factor (SCF), to induce the proliferation and maturation of burst-forming unit erythroid (BFU-E) cells. As these BFU-Es mature, their proliferation becomes increasingly dependent on erythropoietin until as colony-forming unit erythroid (CFU-E) cells, they will only transform into precursor cells in the presence of erythropoietin.
Thus, erythropoietin increases viability and maturation of erythroid progenitor cells.
GM-CSF
IL-3, IGF-1
SCF
Erythropoietin
Erslev & Besarab. Kidney Int. 1997;51:
Erslev AJ, Besarab A. Erythropoietin in the pathogenesis and treatment of the anemia of chronic renal failure. Kidney Int. 1997;51: 6

7. 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 also acts as a survival/maturation factor for erythroid progenitor cells (Polenakovic & Sikole 1996).
Immature erythroid cells are highly dependent on erythropoietin for survival. During the proliferation and differentiation of progenitor cells to mature RBCs, erythropoietin acts to prevent apoptosis before differentiation into committed erythroid precursors (Koury & Bondurant 1990). This is thought to be an important mechanism for regulating steady-state levels of RBCs.
Erythropoietin also appears to be important in preserving the lifespan of newly produced young RBCs (neocytes). In addition, it has been postulated that erythropoietin plays a role in mediating the selective destruction of neocytes (Alfrey et al 1997; Rice et al 1999).
Alfrey CP et al. Neocytolysis: physiological down-regulator of red-cell mass. Lancet. 1997;349:
Koury MJ, Bondurant MC. Control of red cell production: the roles of programmed cell death (apoptosis) and erythropoietin. Transfusion. 1990;30:
Polenakovic M, Sikole A. Is erythropoietin a survival factor for red blood cells? J Am Soc Nephrol. 1996;7:
Rice L et al. Neocytolysis contributes to the anemia of renal disease. Am J Kidney Dis. 1999;33:59-62. 7

8. Erythropoietin : from kidney to bone marrow

9. Erythropoietin Receptor
Membrane
JAK2 P
EPO
Target genes
STAT
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
In the bone marrow, erythropoietin binds to receptors on the surface of erythroid progenitor cells, initiating a signaling cascade which leads ultimately to RBC production.
The erythropoietin receptor is a transmembrane glycoprotein of 508 amino acids belonging to the cytokine receptor super family (Klingmuller 1995). The number of erythropoietin receptors at the surface of erythroid progenitor cells is low, ranging from a few hundred to a few thousand receptors per cell (Lacombe & Mayeux 1999).
In the erythroid lineage, the erythropoietin receptor is most commonly expressed at the CFU-E cell/proerythroblast stage. Erythropoietin receptor numbers diminish during the terminal stages of cell differentiation, with reticulocytes and erythrocytes being completely devoid of receptors (Broudy et al 1991).
Binding of erythropoietin to the receptor leads to receptor dimerisation and autophosphorylation of JAK2 tyrosine kinase. This creates docking sites for several signaling proteins that initiate downstream signaling to the nucleus, activating transcription of various target genes.
Broudy VC et al. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991;77:
Klingmuller U. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995;80:
Lacombe C, Mayeux P. The molecular biology of erythropoietin. Nephrol Dial Transplant. 1999;14(Suppl 2):22-28. 9

10. Regulation of Erythropoiesis Feedback loop
Erythroid marrow
Circulating RBCs
RBCs
Kidney
Erythropoietin O2
The physiologic regulator of RBC production is the glycoprotein hormone erythropoietin, which is produced primarily in the kidney, in response to tissue hypoxia.
Erythropoietin functions as part of a complex feedback loop between the bone marrow and the kidney, and is important in regulating the rate of RBC production.
An optimal RBC mass is maintained via a ‘balance’ between circulating levels of oxygen and erythropoietin.
Under hypoxic conditions, serum erythropoietin synthesis is upregulated. The increased production of erythropoietin increases the synthesis of RBCs.
Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;
Erslev AJ, Beutler E. Production and destruction of erythrocytes In: Beutler E et al, eds. Williams’ Hematology, fifth edition. New York: McGraw-Hill;1995: 10

11. Hb and Erythropoietin: the Non-Anaemic Patient
kidney 2
peripheral Hb
transport
peritubular
hypoxia
capacity
cells
serum EPO O
precursor cells 2
The unique structure of the renal vasculature renders the kidney extremely sensitive to its oxygen supply. In the event of hypoxia in the non-anaemic individual, erythropoietin is produced by the peritubular cells of the kidney, mediated by the hypoxia-inducible factor 1 (HIF-1) complex. This in turn stimulates the production of erythrocytes, raising blood Hb and increasing oxygen transport, providing an efficient feedback mechanism to maintain an optimal supply of oxygen to the tissues.
transport
capacity
erythroblasts Hb
erythrocytes
reticulocytes
EPO=erythropoietin 11

12. Regulation of Erythropoietin Production Normoxia
HIF-1
HIF-1
oxidation OH
Proteosomal degradation
Erythropoietin production is regulated by the transcription factor HIF-1, one of the key regulators of oxygen homeostasis. This heterodimeric protein consists of two subunits, HIF-1 and HIF-1. HIF-1 degrades rapidly under normoxic conditions.
HIF=hypoxia-inducible factor
Jelkmann W. Molecular biology of erythropoietin. Intern Med. 2004;43: 12

13. Regulation of Erythropoietin Production Hypoxia
HIF-1
HIF-1
HIF-1
oxidation
HIF-1 OH
Proteosomal degradation
Hypoxia delays oxidative degradation of HIF-1 allowing binding to HIF-1 and formation of the active HIF-1 dimer. The HIF-1 complex enhances transcription of the erythropoietin gene, increasing erythropoietin production.
EPO gene
Serum EPO
mRNA
Jelkmann W. Molecular biology of erythropoietin. Intern Med. 2004;43: 13

14. Breakdown of Mature RBCs
Extravascular destruction: phagocytic action of fixed macrophages in the liver, spleen, and lymph nodes
As the RBCs have no nucleus or other organelles, they cannot divide or synthesise new cellular components. As a result, they degenerate due to aging and damage to the plasma membranes. Old and damaged RBCs are then removed from the circulation.
The majority are removed from the circulation by the phagocytic activities of macrophages in the liver, spleen, and lymph nodes. Clearly, some signal must allow the macrophage to distinguish between young, healthy cells and their older or damaged counterparts. It is thought that these signals emanate from decreased deformability or altered surface properties.
A small number of cells haemolyse in the circulation; the fragments of these cells are then engulfed by macrophages.
Intravascular destruction: hemolyse in circulation
Erslev AJ, Beutler E. Production and destruction of erythrocytes In: Beutler E et al, eds. Williams’ Hematology, fifth edition. New York: McGraw-Hill;1995: 14

15. 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
Neocytolysis is the selective haemolysis of young RBCs, a physiological process which may allow rapid adaptation when RBC mass is excessive in a new environment.
Neocytolysis was first observed in astronauts, whose RBC mass fell too rapidly to be explained by diminished erythropoiesis, implying that a positive physiological process allows more rapid adaptation to their new environment by selectively haemolysing young RBCs (Alfrey et al 1997; Rice et al 1999).
The underlying mechanism of neocytolysis has not been fully elucidated; however, it has been proposed that the process may be initiated by rapid depression of erythropoietin levels. Thus, it is possible that neocytolysis may contribute to anaemia in patients with already diminished erythropoietin levels, such as those with renal anaemia (Alfrey et al 1997; Rice et al 1999).
Alfrey et al. Lancet. 1997;349:
Rice et al. Am J Kidney Dis. 1999;33:59-62
Alfrey CP et al. Neocytolysis: physiological down-regulator of red-cell mass. Lancet. 1997;349:
Rice L et al. Neocytolysis contributes to the anemia of renal disease. Am J Kidney Dis. 1999;33:59-62. 15

16. The Lifecycle of the RBC
EXCRETION
Macrophage in spleen, liver or red bone marrow
Globin
Amino acids
Heme
Biliverdin
Bilirubin Fe
Circulation
120 days
Fe3+
Transferrin
Ferritin and haemosiderin
Liver
Erythropoiesis in bone marrow
Following production in the bone marrow, mature RBCs survive for about 120 days in the circulation before removal, mainly by phagocytosis by fixed macrophages. Following phagocytosis, the chemical components of the RBC are broken down and either excreted or recycled.
Hb is recycled; the globin portion is broken down into amino acids that may be reused for protein synthesis. The heme portion is broken down into iron and biliverdin. Iron associates with transferrin and is delivered back to the bone marrow for use in the production of new Hb molecules. Biliverdin subsequently converts to bilirubin, which enters the blood and is secreted by liver cells into the bile, which then passes into the gastro-intestinal tract. In the large intestine, bacteria convert bilirubin into urobilinogen, the majority of which is excreted in the faeces. A small amount of urobilinogen is absorbed back into the blood and excreted in the urine.
While the lifespan of the RBC in a healthy individual is approximately 120 days, in a patient with chronic kidney disease (CKD) it may be considerably shortened, contributing to anaemia in these patients (Bonomini et al 2003).
Bonomini M et al. Uremic toxicity and anemia. J Nephrol. 2003;16:21-28. 16

17. 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

18. Causes of Anemia Gender, Age, Race Serious Illness
Malnutrition/ Poverty
Chronic Kidney Disease

19. What is Chronic Kidney Disease (CKD) ?
CKD is the progressive destrution of renal mass, progressive nephrsclerois, reduced nephron units and decreased erythrpeotin leaing to decreased eryhroid precursor cells , decreased maturation of rbc and decreased oxygen carrying system.

20. Anatomy of the Kidney

21. Nephron Network
Filtration
Reabsorption
Secretion

22. 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
Key message
A basic introduction to CKD requires a clear statement of its definition.
Note also the usage of eGFR
This is used for consistency throughout the presentation.
It is important that non-nephrologists become accustomed to the terminology as the CKD Network encourages the use of eGFR
(and not serum creatinine, sCr) in practice to diagnose CKD.
The following slides are devoted to explaining how CKD is staged by eGFR according to the NKF Kidney Disease Outcomes and Quality Initiative (K/DOQI) guidelines of 2002.
For clarity, it may be important to note that the definition of CKD as eGFR <60 mL/min/1.73m2 for ≥3 months is applicable regardless of degree of kidney damage as it is assumed that at this level of eGFR, kidney function has halved.
CKD can also be defined by a ≥3-month duration of kidney damage (pathologic abnormalities or markers of damage such as abnormalities in blood or urine tests or imaging studies).
NKF K/DOQI Clinical Practice Guidelines 2002: Am J Kidney Dis 2002; 39 (2 Suppl 1): S17-S31
NKF K/DOQI Clinical Practice Guidelines 2002: Am J Kidney Dis 2002; 39 (2 Suppl 1): S17-S31

23. Symptoms of CKD

24. CKD: Regulation of Erythropoiesis Disrupted feedback loop
Erythroid marrow
Circulating RBCs
RBCs
Kidney
Erythropoietin O2
In patients with CKD, the kidneys are unable to produce sufficient erythropoietin to stimulate adequate erythropoiesis, leading to anaemia.
Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;
Erslev AJ, Beutler E. Production and destruction of erythrocytes In: Beutler E et al, eds. Williams’ Hematology, fifth edition. New York: McGraw-Hill;1995: 24

25. Hb and Erythropoietin: the Anaemic Patient with CKD
kidney 2
peripheral Hb
transport
peritubular
hypoxia
capacity
cells
DAMAGED
serum EPO O
precursor cells 2
In patients with CKD the ability of the kidney to produce sufficient erythropoietin is reduced. CKD is characterised by progressive destruction of renal mass, irreversible sclerosis and loss of nephrons over a period of months to many years, causing irreparable damage to the renal apparatus essential for erythropoietin production. This leads to insufficient production of erythroid precursors, reduced RBC replenishment, and an overall reduction in oxygen transport capability.
transport
capacity
erythroblasts
ANAEMIA Hb
erythrocytes
reticulocytes
INSUFFICIENT 25

26. Defining Renal Anaemia Erythropoietin levels in patients with non-renal and renal anaemia
Bilateral nephrectomy
Non-renal anaemia
CKD
10 000
1000
100 10 1
Serum EPO (mU/mL) 20 30 40 50 60 70
Haematocrit, %
To be diagnosed with renal anaemia, a patient must have inappropriately low plasma levels of erythropoietin, relative to their degree of anaemia.
Erythropoietin values for healthy individuals and patients with anaemia who have normal kidney function show a clear correlation with the degree of hypoxia (Erslev et al 1980).
In 1979, Caro and colleagues reported serum erythropoietin levels in 25 patients with CKD, 11 of whom had undergone bilateral nephrectomy (Caro et al 1979). In almost all cases, the erythropoietin levels were below levels expected for patients with anaemia not related to kidney function.
Nevertheless, in some patients with CKD, erythropoietin levels can be normal or even higher than those seen in healthy individuals (Erslev & Besarab 1995). This is thought to be a consequence of decreased response in the bone marrow to erythropoietin.
Adapted from Caro et al. J Lab Clin Med. 1979;93:
Caro J et al. Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med. 1979;93:
Erslev AJ et al. Plasma erythropoietin in health and disease. Ann Clin Lab Sci. 1980;10:
Erslev AJ, Besarab A. The rate and control of baseline red cell production in hematologically stable patients with uremia. J Lad Clin Med 1995;126: 26

27. 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
Erythropoietin is critical for the continued replenishment of erythrocytes. However, in individuals with CKD, the inability of the kidneys to produce sufficient erythropoietin to stimulate adequate erythropoiesis almost invariably results in normocytic, normochromic anaemia, which can be characterised by RBCs that are normal in morphology and Hb content, but are too few to sustain adequate oxygen transport. This can be compounded by a reduction in the lifespan of circulating erythrocytes. In healthy individuals, the lifespan of an erythrocyte is 120 days, but this may fall to days in uremic patients.
Renal anaemia can be exacerbated by other anaemia-inducing factors, including iron deficiency (Parker et al 1979), severe hyperparathyroidism (Potasman & Better 1983), acute and chronic inflammatory conditions (Adamson & Eschbach 1989), aluminium toxicity (Kaiser & Schwartz 1985), folate deficiency (Hampers et al 1967), hypothyroidism (Eschbach 1995), and less commonly, haemoglobinopathies (Kausz et al 2001).
†anaemia characterised by RBCs which are normal in morphology and Hb content, but are too few to sustain adequate oxygen transport
Adamson JW, Eschbach JW. Management of the anaemia of chronic renal failure with recombinant erytropoietin. Q J Med. 1989;73:
Eschbach JW. The future of R-HuEPO. Nephrol Dial Transplant. 1995;10(Suppl 2):
Hampers CL et al. Megaloblastic hematopoiesis in uremia and in patients on long-term hemodialysis. N Engl J Med. 1967;276:
Kaiser L, Schwartz KA. Aluminium-induced anemia. Am J Kidney Dis. 1985;6:
Kausz AT et al. Management of patients with chronic renal insufficiency in the Northeastern United States. J Am Soc Nephrol. 2001;12:
Parker PA et al. Therapy of iron deficiency anemia in patients on maintenance dialysis. Nephron. 1979;23:
Potasman I, Better OS. The role of secondary hyperparathyroidism in the anemia of chronic renal failure. Nephron. 1983;33: 27

28. Kidney Diseases
Glomerulonephritis
Polycystic Kidney Disease

29. Hypertension and CKD

30. Diabetes and CKD

31. Diabetes and Anaemia Diabetes Anaemia Nephropathy (35%) CKD
↓Serum EPO level
Neuropathy (50%)
Diabetes
Anaemia
↓Serum EPO response
Hyperglycaemia
It is now known that there is a clear link between diabetes and renal anaemia. Approximately 35% of patients with diabetes eventually develop diabetic nephropathy. Damage to the basement membrane of the glomeruli ultimately results in CKD, decreased production of erythropoietin and anaemia. The onset of anaemia can occur early in the course of CKD in patients with diabetes.
Some 50% of patients with diabetes will also develop diabetic neuropathy. The relationship between this condition and anaemia has only recently emerged, with a number of studies showing blunted erythropoietin response to anaemia in diabetic patients. It has been suggested that renal denervation, combined with damage to erythropoietin-producing fibroblasts in the renal cortex, contributes to the early development of anaemia in patients with diabetes.
Hyperglycaemia is known to affect the function of nerves and muscles, and possibly other tissues. It has been postulated that erythropoietin responses in hyperglycaemic conditions may be blunted, possibly due to glycosylation of both low-density lipoprotein (LDL) and the LDL receptor, leading to a failure in mutual recognition.
To add to this, RBC abnormalities may result from the assembly of plasma membranes in a high-glucose environment, and advanced glycosylation end-products may accumulate on the RBC membrane, enhancing its interaction with the endothelium. Both of these mechanisms will shorten the lifespan of the RBC, exacerbating anaemia.
RBC abnormalities
↓ RBC survival 31

32. 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
As a chronic condition, renal anaemia has a number of pathophysiological effects. The most recognised of these are cardiovascular effects brought about as compensatory mechanisms become deleterious to cardiac function. These conditions can be worsened by hypertension and fluid overload, both of which are common in patients with CKD.
Changes in cardiac physiology coupled with possible alterations in skeletal muscle metabolism will, in turn, lead to reduced exercise capacity. Some patients may adapt over time, but the majority demonstrate impaired exercise tolerance.
Patients may also be aware of other symptoms, including loss of appetite, angina, palpitations, tachycardia, increased sensitivity to cold, menstrual irregularity, reduced libido, dizziness and pallor.
It is widely recognised that anaemia correlates with a diminished quality of life (QoL). In addition, objective neurophysiological tests have revealed diminished brain and cognitive function in patients with renal anaemia, and there is evidence of impaired endocrine, sexual and immune function. 32

33. Reciprocal Relationships: Diabetes, CKD, CVD, and Anaemia
Both diabetes and anaemia contribute to significant morbidity and mortality associated with CKD. The contribution of anaemia to the comorbidities associated with diabetes is not yet completely understood. However, both CKD and anaemia are known to contribute to CVD, and this risk is clearly exacerbated in patients with diabetes, who are two to four times more likely to have heart disease or suffer a stroke. Approximately 75% of patients with diabetes die of CVD-related causes.
CVD
CVD=cardiovascular disease 33

34. 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
A number of major studies emphasise the link between CKD, anaemia and an increased risk of cardiac disease and mortality.
One study followed 433 patients with stage 5 CKD from the start of dialysis for a mean of 41 months. At the beginning of the study, clinical manifestations of cardiovascular disease (CVD) were already highly prevalent in these patients; 31% had cardiac failure, 19% had angina pectoris and 14 had coronary artery disease (CAD). In addition, echocardiography shows that 15% of patients had systolic dysfunction, 32% had left ventricular dilatation and 74% had LVH (Foley et al 1995).
The investigators also reported on the impact of anaemia on echocardiographic abnormalities, cardiac morbidity and mortality (Foley et al 1996). After adjusting for age, diabetes ischaemic heart disease, blood pressure, and serum albumin levels, each 1 g/dL decrease in mean Hb level was independently associated with the presence of LVH (odds ratio 1.46, P=0.018), the development of de novo cardiac failure (relative risk [RR] 1.28, P=0.018) and the development of recurrent cardiac failure (RR 1.20, P=0.046). Each incremental drop in Hb level was also independently associated with mortality.
1. Foley et al. Kidney Int. 1995;47:
2. Foley et al. Am J Kidney Dis. 1996;28:53-61
Foley RN, et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int. 1995;47:
Foley RN et al. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28:53-61. 34

35. Anemia, Heart Disease and CKD

36. The Cardio-Renal Anaemia Syndrome A vicious circle
Hypoxia
CKD
Anaemia
Serum EPO production Apoptosis
Cardiacoutput
Fluid retention
Renal vasoconstriction
Uraemia
Sympathetic activity
TNF-α
Hypoxia
Cardiac disease, CKD and anaemia are interconnected in a complex way, termed the cardio-renal anaemia syndrome.
In a patient with anaemia, associated hypoxia leads to peripheral vasodilatation, decreased vascular resistance and reduced blood pressure. To maintain blood pressure, peripheral vasoconstriction, heart rate and stroke volume are all increased through elevated sympathetic activity. However, this also leads to renal vasoconstriction, resulting in a reduction of blood flow to the kidney, a reduction in glomerular filtration rate (GFR) and renal ischemia. This can be aggravated further by the renin-angiotensin aldosterone system.
The outcome is fluid retention (Anand et al 1993) and an increase in plasma volume, which causes left ventricular hypertophy (LVH), leading to necrosis and apoptosis of myocardial cells. Excessive renin, angiotensin, and aldosterone can also destroy cardiac cells directly (Katz 1994; Johnson & Dell’Italia 1996). The result is congestive heart failure (CHF).
Levels of tumour-necrosis factor-alpha (TNF-) are increased in CHF. Increased production of cytokines such as this has been implicated in the development of renal anaemia (Torre-Amione et al 1999), and may also worsen the anaemia in patients with CKD and CHF, completing a vicious cycle of disease progression.
CHF
CHF=congestive heart failure
Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47
Anand IS et al. Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones. Br Heart J. 1993;70:
Johnson DB, Dell’Italia LJ. Cardiac hypertrophy and failure in hypertension. Curr Opin Nephrol Hypertens. 1996;5:
Katz AM. The cardiomyopathy of overload: an unnatural growth response in the hypertrophied heart. Ann Intern Med. 1994;121:
Torre-Amione G et al. An overview of tumor necrosis factor alpha and the failing human heart. Curr Opin Cardiol 1999;14:
Silverberg DS et al. Erythropoietin should be part of congestive heart failure management. Kidney Int Suppl. 2003;(87):S40-S47 36

37. 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
Erythropoietin, a glycoprotein hormone produced predominantly in the kidney, is the key regulator of RBC production in the bone marrow, and is produced in response to tissue hypoxia.
In individuals with CKD, damage to the kidney compromises its ability to produce sufficient erythropoietin, resulting in anaemia. Thus CKD almost invariably leads to anaemia which worsens with the progression of the CKD.
In addition to a recognised effect in reducing QoL, anaemia is linked with a number of cardiovascular effects, including increased prevalence of LVH, CHF, CAD and mortality, and strong interrelationships exist between CKD, anaemia and CVD. 37