Adam Rumjon and Iain Macdougall - Review Date October 2015 (Senior Editor Pete Topham)
Anaemia is a common and debilitating complication of chronic kidney disease that is seen in over 80% of patients with advanced renal impairment (Melnikova, 2006). Characteristically it is normochromic normocytic anaemia, with a low reticulocyte count. The haemoglobin level may fall to 6-8 g/dl, untreated, in ESRD patients.
To date, no studies have rigorously proven that anaemia in CKD causes an increase in mortality. However, a number of observational stuides have shown an association between degree of anaemia in CKD and an increased risk of death. Foley et al (1996) prospectively followed 432 ESRD patients and found that each 1 g/dl increase in haemoglobin was associated with a 14% decrease inmortality risk.
Furthermore,regarding morbidity, Collins (2001) found the risk of hospitalisation was lower inHD patients with higher haemoglobin levels. The Canadian EPO study (and others that followed)showed that correction of anaemia in CKD improves Quality of Life (CESG, 1990). Non-controlled studies have suggestedthat correction of anaemia improves cognitive functions and sleep. Controlled studies have not shown that correction of anaemia corrects left ventricular hypertrophy (Foley, 2000).
Erythropoietin (EPO) deficiency is the primary underlying defect in the anaemia of CKD. Most EPO is made in the kidney, and the primary site of action is in the erythroid tissues of the bone marrow. The fact that EPO is detectable after bilateral nephrectomy is consistent with the experimental finding that 10% is produced by the liver.
Human erythropoietin is a sialglycoprotein composed of 165 amino acids. Human erythropoietin was purified in 1977, and the human erythropoietin gene was isolated by Lin in 1985. Recombinant human erythropoietin (rHuEPO) therapy was introducedin 1986-7 (Winearls, 1986; Eschbach, 1987). Before then, dialysis patients were the frequent recipients of blood transfusions approximately every 2-3 weeks. This, however, subjected patients tocomplications such as blood-borne viruses, iron overload and increased sensitivity to major histocompatibility antigens, lessening the chances for successful kidney transplantation.
Anaemia is defined as a state in which there is a reduced number of circulating red blood cells. Blood haemoglobin (Hb) concentration serves as the key indicator for anaemia because it can be measured directly, has an international standard, and is not influenced by differences in technology.
A previously established definition of anaemia constitutes a haemoglobin concentration lower than the established cut off defined by the World Health Organization (WHO, 2001), and different biological groups have different cut-off haemoglobin values below which anaemia is said to be present. This cutoff figure varies from 11 grams per decilitre (g/dl) for pregnant women and for children between 6 months and 5 years of age, to 12 g/dl for non-pregnant women, and to 13 g/dl for men. No downward adjustment for the elderly is made for age. Furthermore there is accumulating evidence that anaemia reflects illness and is associated with adverse outcomes in the elderly (Guralnik, 2004).
Target Haemoglobin and Iron Stores
The issue of haemoglobin targets has long been a contentious issue amongst clinicians (Macdougall, 2001)and this is reflected in the disparity among the numerous clinical anaemia guidelines (in references). In addition to therapy with erythropoiesis-stimulating agents (ESAs), iron therapy is also a mainstay of treatment in the end-stage renal disease (ESRD) patient population; since iron is an essential ingredient for the synthesis of heme - and the subsequent production of red blood cells. Again, there is controversy regarding the appropriate target ranges for markers of iron status in ESRD patients.
The UK information concerning the prevalence of anaemia in patients with CKD comes from two studies (John, 2004; De Lusignan, 2005). The first of these population studies (John, 2004) examined the prevalence of CKD, defined as having a serum creatinine level of ≥130 μmol/l in women and ≥180 μmol/l in men, and found a rate of 5,554 per million population (pmp), with a median age of 82 years (range, 18 to 103 years), and a median calculated GFR of 28.0 ml/min/1.73m2 (range, 3.6 to 42.8 ml/min/1.73 m2).
Data for haemoglobin levels were available for 85.6% of patients. Mean haemoglobin concentration was 12.1±1.9 g/dl: 49.6% of men had haemoglobin levels less than 12 g/dl and 51.2% of women had levels less than 11 g/dl. Furthermore, in 27.5% of patients identified, the haemoglobin level was less than 11 g/dl, equivalent to nearly 90,000 of the population based on 2001 Census population figures.
The second, and larger, cross-sectional study abstracted data from 112,215 unselected patients with an age and sex profile representative of the general population (De Lusignan, 2005). Haemoglobin level was weakly correlated with eGFR (r=0.057, p <0.001). The population prevalence of stage 3–5 CKD in this study was estimated to be 4.9%. In those patients with stage 3–5 CKD, the prevalence of anaemia (defined as a haemoglobin level less than 12 g/dl in men and post-menopausal women, and less than 11 g/dl in pre-menopausal women) was 12.0%. Haemoglobin level was less than 11 g/dl in 3.8%, equivalent to over 108,000 of the population based on 2001 Census population figures.
First recorded in 1824. Derived from French medical term (1761), from Modern Latin, from Greekanaimia ('lack of blood'), from anaimos ('bloodless'), from an- ('without')+haima ('blood').
Chronic kidney disease affects only the red cell lineage, and typically produces a normocytic and normochromic anaemia, without leucopenia or thrombocytopenia. The lifespan of these red blood cells is reduced, as is the rate of production by the bone marrow. Although there are many mechanisms involved in the pathogenesis of renal anaemia, the primary cause is thought to be the inadequate production of erythropoietin (Chandra, 1988).
EPO is made in the peritubular interstitial cells of the kidneys, and its production is stimulated by hypoxia. EPO stimulates red cell production through binding to homodimeric EPO receptors that are primarily located on early erythroid progenitor cells, the burst-forming units erythroid (BFU-e) and the colony-forming units erythroid (CFU-e). Inhibition of red cell production by uraemic inhibitors of erythropoiesis may also contribute to the pathogenesis of renal anaemia (Macdougall, 2010).
Other factors in the genesis of renal anaemia include functional or absolute iron deficiency, blood loss (either occult or overt), the presence of uraemic inhibitors (Macdougall, 2001) (for example, parathyroid hormone, inflammatory cytokines), reduced half-life of circulating blood cells, and deficiencies of folate or vitamin B12. The lifespan of healthy RBCs is around 120 days, but is reduced to 60-90 days in uraemic patients.
Causes of Anaemia in CKD
- EPO deficiency
- Chronic blood loss (via GI tract/haemodialyser)
- Iron deficiency
- Vitamin B12 or folate deficiency
- Chronic infection or inflammation
- Chronic blood loss
- Aluminium toxicity
- Bone marrow infiltration
- Pure red cell aplasia
This article by Steven Brunelli in 2009 is a good summary of the pathogenesis of renal anaemia
Clinical Effects of Anaemia
- Decreased exercise capacity
- Exertional dyspnoea
- Cognitive impairment
- Diminished quality of life
- Poor memory
- Reduced libido
- Poor sleep pattern
- Reduced immune function
- Reduced platelet function
- Increased cardiac output/stroke volume
- Decreased vascular resistance
- Worsening of pre-existing anginal symptoms/myocardial ischaemia
- Left ventricular hypertrophy
- Impairment in nitric oxide synthesis
- Limited oxygen reserve
- Abnormal angiogenesis
The current algorithm used in the UK for the diagnosis and initiation of treatment in renal anaemia was issued by the National Institute for Health and Clinical Excellence (NICE) in February 2011 (NICE, CG114).
The tests that one should request in order to evaluate anaemia in CKD are as follows:
- Full blood count
- Haematinics (B12, folate and ferritin)
- Absolute reticulocyte count
- Percentage hypochromic red blood cells (PHRC)
- Transferrin saturation
Consider three concomitant medical problemsif the degree of anaemia is disproportionate to the degree of renal impairment, especially:
- Haemoglobinopathy (HbSS, HbSC disease, thalassaemia)
- Drug therapy (there are many drugs that can cause anaemia - examples include ACE-inhibitors, azathioprine and mycophenolate mofetil)
- Bone marrow infiltration (myeloma, myelodysplastic syndrome)
Problems with Quantifying Iron Status in CKD
Iron metabolism involves storage and transfer to the bone marrow for erythropoiesis.The various biochemical tests that are currently available to test for iron availability at different stages in the iron cycle, from stored iron to circulating iron, are descibed below. However, even if a patient has an adequate amount of stored or circulating iron, they may still not present enough iron to the erythroid cells for sufficient RBC production.
The increasing prevalence of multiple comorbidities among anaemic patients with chronic kidney disease has made the use of serum ferritin and transferrin saturation more challenging in diagnosing iron deficiency. Because serum ferritin is an acute-phase reactant, the scenario of patients with serum ferritin >800 ng/ml (suggesting iron overload) and transferrin saturation <20% (suggesting iron deficiency), has become more common (Wish, 2006).
Low serum ferritin concentrations unequivocally determines absolute iron deficiency (Macdougall, 1994). In patients with chronic renal failure, higher cut-off values have been suggested. Ferritin measurements in dialysis patients are subject to a significant degree of variability; and so it is preferable to have multiple measurements to assess true ferritin levels (Ford, 2009).
Like ferritin, transferrin saturation (TSAT, which is calculated by the following formula: TSAT = serum Fe ÷ TIBC (total iron binding capacity) x 100%) also has some acute-phase reactivity (and is also elevated in inflammation). Transferrin may be low because of decreased transferrin synthesis in the setting of malnutrition and chronic disease, which would raise TSAT if circulating iron were constant. There also are significant (17 to 70%) diurnal fluctuations in TSAT that make it difficult to interpret its value if the time of day at which the test is obtained varies from test to test(Kalantar-Zadeh, 2004).
Percentage Hypochromic Red Cells (%HRC)
Iron deficient erythrocytes are hypochromic (individual erythrocyte hemoglobin concentration < 28 g/dL) and microcytic. %HRC has been shown to be a sensitive and early marker of functional iron deficiency (Macdougall, 1994).
Like both ferritin and TSAT, hepcidin is an acute-phase protein that (as its name suggests) is produced by the liver, and is elevated in inflammatory states. It has also been shown to be elevated in advanced kidney disease (Rumjon, 2012). Hepcidin blocks iron absorption from the gastro-intestinal tract, and this in part may explain why oral iron is poorly absorbed in uraemic individuals. Hepcidin also locks iron in the reticulo-endothelial system and may contribute to functional iron deficiency (Ganz, 2006). Its utility as a marker of iron status has been investigated; and it is also subject to significant intra-individual variability in dialysis subjects (Ford, 2010). It may be better as a marker of patient response to iron therapy rather than as an indicator of absolute iron stores.
Summary of Markers of Iron Status in CKD Patients (recommended range in brackets) (Macdougall, 2010)
- Serum ferritin (100-500 g/L (CKD); 200-500 g/L(HD))
- Transferrin saturation (20-40%)
- Hypochromic red cells (<10%)
- Reticulocyte Hb content (>29 pg/cell)
- Serum transferrin receptor (not established)
- Erythrocyte zinc protoporphyrin (not established)
What is Functional Iron Deficiency?
Absolute iron deficiency refers to the depletion of iron stores and the absence of stainable iron in the bone marrow. Whereas functional iron deficiency is a clinical condition where stored iron is sufficient but circulating iron is deficient. It can occur when erythropoiesis stimulating agent (ESA) therapy stimulates red blood cell production beyond the available supply of iron necessary for Hb synthesis. It can also be caused by chronic inflammation (Wish, 2006). Elevated serum ferritin and TSAT <20% may indicate functional iron deficiency.
The Effect of Blood Transfusions on Red Cell Indices
Following a blood transfusion, measurement of red cell indices and markers of iron status are immediately distorted by the presence of a new population of red cells. Thus, the MCV, MCH, MCHC, and %HRC will be a composite of the patient’s own red cell characteristics, and those of the transfused donor cells. The red cell width (RDW) will be increased accordingly, while serum ferritin and TSAT will be spuriously increased. Given that the lifespan of the transfused red cells is 90-120 days, it will be 3-4 months before the natural steady state is restored.
Increase the Adequacy of Dialysis
Increasing the dialysis prescription has been shown to augment the response to ESA therapy (Ifudu, 1996).
Correction of Haematinic Deficiency
Folate (and less commonly vitamin B12) is a low molecular weight substance that may be lost during haemodialysis (especially high-flux) (Macdougall, 2003). Serum folate is not as accurate as red cell folate level, as a marker of folate deficiency, but is the most commonly used initial screening test.
The causes and diagnosis of iron deficiency in CKD are listed above. If a patient is considered deficient in iron, then there are a number of iron preparations (both oral and intravenous) that are available.
Erythropoiesis-Stimulating Agents (ESAs)
EPO is a large glycoprotein (30.4 KDa) that is injected intravenously (HD patients), or subcutaneously (Kaufman, 1998). Current UK guidance recommends starting therapy when the Hb falls below 11 g/dl, but of late there has been a tendency for lower Hb’s to be accepted before intervening with ESA therapy following data from the TREAT trial (see Key Clinical Trials). ESA therapy is effective in correcting anaemia in the vast majority of patients, with 5-10% of patients deemed ESA hyporesponsive.
Complications of ESA Therapy
- Increased AV graft clotting
- Pure red cell aplasia
Causes of ESA Hyporesponsiveness (Macdougall, 2003)
|Iron deficiency||Aluminium toxicity|
|Inadequate dialysis||B12/folate deficiency|
|||Bone marrow disorders|
|||Anti-EPO antibodies = PRCA (pure red cell aplasia)|
Normal Hematocrit Study (Besarab, 1998)
• Open-label trial of 1233 HD patients with heart failure/IHD
• Epoetin given either to maintain a normal (42 ±3 %) or low (30 ±3 %) haematocrit
• Primary endpoint – MI/death
• Study was stopped after 29 months due to the higher (albeit non-statistically significant) death rate in the normal haematocrit group – 183 vs 150 deaths
Note: this study raised concerns regarding the risks of trying to attain a higher level of haemoglobin
CHOIR (Singh, 2006)
• Open-label trial of 1432 CKD patients randomised to either a low-Hb (11.3 g/dl) or high-Hb arm (13.5 g/dl)
• Primary endpoints included death and CV events (and CVA)
• 125 events occurred among the high-Hb group and 97 events among the low-Hb group (HR 1.34; P = 0.03)
• No quality-of-life difference between the two groups
CREATE (Drueke, 2006)
• Multicentre trial of 603 CKD patients randomised to high-Hb (13.0-15.0 g/dl) or low-Hb (10.5-11.5 g/dl)
• No difference between groups in terms of primary endpoints (CV/death)
• Study ended up being underpowered
TREAT (Pfeffer, 2009)
• Multicentre, double-blind, placebo-controlled RCT
• Darbepoetin (Aranesp) (aiming for Hb 13 g/dl) vs placebo* (Hb of 9 g/dl) in 4038 predialysis CKD patients with type 2 diabetes and anaemia
• No difference in primary CV endpoint/death
• Improved symptoms in treatment arm
• Two-fold increased risk of CVA in treatment arm
• Death from cancer higher in ESA group (7.4% versus 0.06%, P=0.002)
• More iron therapy administered to the placebo group
(*with rescue ESA therapy to maintain an Hb of 9 g/dl, which was subsequently discontinued once Hb > 9 g/dl)
Top Tips: Consider an ESA in any CKD patient with Hb <11 g/dL. Keep Ferritin >200 ng/L
- There is no worldwide consensus concerning target ranges for haemoglobin and iron/ferritin levels. The new KDIGO renal anaemia guidelines are expected in mid-late 2012
- Functional iron deficiency occurs when stored iron is sufficient but circulating iron is deficient. It may be detected when serum ferritin levels are decreased and TSAT levels are <20%, but this is not a hard and fast rule
- TSAT (transferrin saturation) is calculated by the following formula: Serum Fe ÷ TIBC x 100%
- Blood transfusions distort patients’ red cell indices, and it can take 3-4 months for the normal steady state to be resumed
- Treatment includes Erythropoiesis-Stimulating Agents (ESAs), correcting iron deficiency, treating infection/inflammation and increasing dialysis dose
- Major causes of ESA hyporesponsiveness are iron deficiency, inflammation/infection and inadequate dialysis
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