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Anaemia in kidney disease explained

skypixel/dreamstime.comThe UK Renal Association (UKRA) has advised GPs that eGFR in a healthy young adult is around 100ml/min/1.73m2. Chronic kidney disease (CKD) is categorised as a sustained reduction in glomerular filtration rate (although an eGFR above 60ml/min/1.73m2 is not considered CKD unless there is other evidence of kidney damage). As the disease progresses the kidney cannot perform its usual excretory and metabolic functions. As a result, patients typically develop a range of problems, including oedema due to oligouria, hypertension (although this can precede the CKD) and derangements in blood chemistry. These have been well described elsewhere,1 and can be managed with a variety of oral therapies.

Anaemia is also anticipated in CKD. It is considered to be a blood haemoglobin of <13g/dl or <12g/dl in premenopausal women (normal values could be between 12 and 18g/dl depending on age and sex). Anaemia typically presents as tiredness and weakness but, as it progresses, it leads to breathlessness, exacerbation of cardiovascular disease symptoms, and psychological effects such as apathy and depression.

The UKRA recognises that, as CKD progresses, anaemia is likely although other causes of anaemia should not be discounted.2 In CKD patients anaemia is usually ascribed to a failure of the kidneys to secrete erythropoietin, but must be investigated to exclude other serious causes, such as malignancy, and to avoid using erythropoiesis-stimulating agents (ESAs) inappropriately, inefficiently or ineffectively.

In CKD, anaemia may simply result from iron deficiency. Dietary restrictions or anorexia resulting from uraemia can reduce oral iron intake. In addition, concurrent administration of calcium- and aluminium-containing phosphate binders and proton pump inhibitors (commonly prescribed

in CKD) can reduce the absorption of dietary or supplemental iron, which is already impaired in CKD. Iron deficiency can also develop once ESA (see Panel 1) therapy is initiated; the resulting manufacture of erythrocytes requires iron to form haemoglobin.

Panel 1: Role of erythropoietin

Erythropoietin is a protein hormone manufactured in the peritubular cells of the kidney in response to a drop in blood oxygenation. When it reaches the bone marrow, in the presence of adequate iron it promotes the increased production of erythrocytes. Once a sufficient haemoglobin level is achieved, the resulting increase in oxygen availability turns off erythropoietin secretion, preventing the blood becoming too rich in erythrocytes. Athletes exploit this mechanism by training in hypoxic conditions such as those found at altitude to generate rises in haemoglobin that enhance performance on return to lower altitudes. Alternatively, dishonest athletes may be tempted to use synthetic erythropoietin to achieve the same result, although it has been implicated in deaths due to rises in blood pressure and blood viscosity, aggravated by dehydration during exertion.3

This altitude-related effect on erythropoiesis was long known, although erythropoietin was only isolated in the 1970s. In 1989 synthetic human erythropoietin, epoetin, was licensed in the UK. Initially available as epoetin-alfa (Eprex) and epoetin-beta (NeoRecormon), these products were almost identical to natural human erythropoietin and revolutionised the management of haemodialysis patients, the most anaemic cohort in CKD. It was administered three times a week by intravenous or subcutaneous injection although the latter was soon found to be more effective and cheaper. In 2001 Amgen launched darbepoetin alfa (Aranesp) offering a much reduced dosing frequency and no loss of efficiency when used intravenously. Finally Mircera, methoxypolyethylene glycol-epoetin beta, is an ultra-long half-life product that can be given as infrequently as monthly in some patients. Collectively, all these products are known as erythropoiesis-stimulating agents.

Minor gastrointestinal bleeds (stress ulceration) increase in chronic conditions such as CKD and many patients lose blood and therefore iron. Furthermore, patients who have started haemodialysis in end-stage disease have chronic blood losses on repeated haemodialysis, even if there is no major bleed or clot in the blood circuit. Chronic blood loss may also result from repeated blood sampling.

Even in the presence of adequate iron stores, patients can struggle to maintain serum haemoglobin. Patients may be deficient in folate or vitamin B12, possibly aggravated by losses during haemodialysis. Chronic inflammation or infections, uraemia and other metabolic abnormalities impair the function of the bone marrow. It is known that the survival of red blood cells in the circulation is reduced in CKD, meaning greater erythropoiesis is constantly required to maintain haemoglobin.

Use of ESAs

If ESAs are required, the choice of ESA is probably less important than using a product well. Many European patents for epoetin have now expired, and a variety of biosimilars have been launched in recent years. Biosimilars are not exactly the same as the original products and therefore may have less of a safety track record, and not all have a subcutaneous licence. When ESAs first became available, they were expensive products costing £3,000–£4,000 per patient annually, and nephrologists adopted strategies to reduce costs, including avoiding intravenous use of epoetin, dispensing using FP10(HP) forms or through GPs to avoid VAT, restricting patient entitlement and reducing target haemoglobin levels. In the past five years, manufacturers have shown willingness to discount prices aggressively for bulk purchasing by renal units. This has led to trusts being able to purchase ESAs at a fraction of the NHS list price, and an increasing move towards centralisation of supply. Manufacturers are also expected to cover or subsidise the costs of refrigerated delivery to the homes of non-haemodialysis patients.

Most centres have a protocol for renal anaemia management based on National Institute for Health and Clinical Excellence and UKRA guidelines.2,4 This includes when to investigate and treat renal anaemia (in adults usually when haemoglobin falls to <11g/dl), the exclusion of other serious diseases and the correction of exacerbating factors. The local choice ESA is then initiated. Epoetins are initially dosed twice to three times a week depending on product and patient type, darbepoetin weekly to fortnightly, and Mircera monthly. Doses are titrated monthly upwards and downwards to keep haemoglobin rising but at no more than 2g/dl until the target haemoglobin is achieved, and then maintenance phase dosing is adjusted to keep it in the target range. Blood pressure, serum haemoglobin and iron studies are measured throughout treatment.

It was soon recognised that ESAs improved quality of life and wellbeing scores in CKD, and reduced the need for blood transfusions, especially in patients receiving haemodialysis. Reductions in cardiac hypertrophy were also reported, and a reduction in the previous mortality that results from living with profound anaemia (<10g/dl). ESA therapy did further increase blood pressure — a problem in CKD — and it is now known that progression of malignancies may be increased. One rare problem that was recognised early on was the development pure red-cell aplasia (PRCA). In PRCA, formation of anti-ESA antibodies results in a worsening anaemia resistant to ESA therapy. The only solution is to cease ESA therapy. PRCA in one product was attributed to an interaction with its syringe/bung, especially on subcutaneous use, but PRCA should not be excluded as a possibility with any ESA.

The dramatic effect of ESAs on anaemia should not be underestimated and younger professionals may not appreciate the revolution in anaemia management over the past 15 years. However, evidence of improvements in mortality from raising haemoglobin above the minimum to relieve symptoms has proved elusive. In 1998, The Normal Haematocrit Study,5 which involved 1,200 haemodialysis patients at high cardiovascular risk, showed an unexpected and counterintuitive increase in deaths in patients with a higher target haematocrit equating to a haemoglobin of 14g/dl than one equating to 10g/dl. Then, in 2006, two further studies showed clearly that driving haemoglobin too high with ESAs has little benefit and may be unsafe.

Both CREATE (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin-beta)6 and CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency)7 studied large numbers of pre-dialysis CKD patients and treated some to “normal” targets (13g/dl or more) while others aimed for a lower target of about 11g/dl. Results showed that quality of life benefits were marginal at best, whereas ESA costs were almost doubled. CHOIR, in particular, showed a much higher rate of composite end point (ie, death, congestive cardiac failure, hospital admission, myocardial infarction or stroke) in the higher target cohort.

In 2009, TREAT (Trial to Reduce cardiovascular Events with Aranesp Therapy)8 reported randomising 4,000 diabetic and anaemic CKD stages 3 to 4 patients to a target of 13g/dl using darbepoetin or placebo, only treating the latter group if haemoglobin plummeted. Mortality and cardiac events were much the same in both groups but strokes almost doubled in the treated group. There was a much greater chance of dying from a pre-existing malignancy and only a modest improvement in quality of life. It is interesting that a later subgroup analysis showed that rather than risk being simply a factor of achieved haemoglobin, it was those who responded poorly initially to therapy and needed larger doses who fared worst. The significance of these events and whether they can be extrapolated have been debated but guidelines and licences have since been modified to avoid overtreatment with ESAs, which becomes more likely as costs fall and use increases.

It seems clear that although uncontrolled renal anaemia is associated with mortality and morbidity risks and can be prevented with ESAs and iron, the target haemoglobin for optimum benefits, risks and costs is much lower than a “normal” haemoglobin. Since 2011, NICE has recommended (for adults and children over two years of age) that haemoglobin should be maintained in the range 10–12g/dl if ESAs are used, taking action at 10.5–11.5g/dl to avoid straying outside these outer bands.1 NICE sets this range because it would be difficult to maintain a whole patient population within a narrower target. Individual targets should consider co-morbidities and level of treatment required, involving patients in discussions of risks versus benefits. NICE does also say that lower haemoglobin levels should be considered acceptable if high doses of ESA are required to achieve them, or if dose escalation is not working. Similarly, higher haemoglobin levels can be accepted if they are achieved using iron therapy alone, or develop on low ESA doses, or if there is a clinical benefit sought in patients with low stroke risk (eg, younger adults in physical jobs). Adequate iron stores are required for effective therapy, and any of the exacerbating factors that worsen anaemia or impair response to ESAs should be addressed to ensure optimum control at lowest doses of ESA therapy.

Key points

  • Anaemia is a common facet of chronic kidney disease, most often due to a failure of the kidneys to synthesise or secrete erythropoietin. It can also be caused by CKD-related iron deficiency.
  • Anaemia presents as tiredness and weakness but it can also lead to breathlessness, exacerbation of cardiovascular disease symptoms, apathy and depression.
  • Anaemia caused by chronic kidney disease is treated with erythropoiesis-stimulating agents (ESAs). To ensure optimum control at the lowest doses of ESA, oral or intravenous iron may also be given.

Iron management

Erythropoiesis cannot proceed without adequate iron for haemoglobin manufacture. Iron stores should be corrected before initiating ESA therapy to avoid wasting ESA; adequate iron may improve serum haemoglobin in CKD if iron deficiency has been a major cause. NICE says that, in general, serum ferritin, reflecting stored iron (to avoid absolute iron deficiency) should be 200–500µg/L. If possible, transferrin saturation, which reflects available iron, should be above 20 per cent to avoid functional iron deficiency, or alternatively percentage hypochromic cells kept below 6 per cent, so long as serum ferritin does not have to be raised too far to achieve these. Oral iron may be sufficient for some patients using a tolerated preparation, but once ESA therapy is under way, especially in haemodialysis patients who have greater blood losses, intravenous iron will be required. Hypersensitivity reactions are rare but possible, especially on first dosing.

As with ESAs, although there are marginal differences between different intravenous irons, all the products available in the UK will achieve the desired result. Iron dextran (Cosmofer) was traditionally popular, and can be given in “total-dose” infusions on a one-off basis, though these take several hours to administer. Many units use iron sucrose (Venofer), which can be administered regularly by intravenous infusion or injection in a dose titrated to the patient’s needs. Use of iron sucrose in non-HD patients (pre-dialysis and peritoneal dialysis) is hindered by the maximum single dose of 200mg, meaning repeated clinic or domiciliary visits to get a typical 1g dose into an outpatient. Although more expensive, the newer preparations ferric carboxymaltose (Ferrinject) and iron isomaltoside (Monofer) are taking market share since the 1g dose can be given in a short infusion, saving health workers’ time and improving the patient experience. A new product launched last month, ferumoxytol (Rienso [see New product focus]) can be injected in seconds but its current licensed maximum dose of 500mg per visit will limit its attraction for outpatient use.

About the author

John Sexton, MSc, MRPharmS, is principal pharmacist lecturer-practitioner at Royal Liverpool and Broadgreen University Hospitals NHS Trust and Liverpool John Moores University


Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11115469

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