Causes of anaemia
Plasma EPO levels are within the ‘normal’ range (6–30 mU/ml), but not increased to the levels seen in other severe anaemias (>100 mU/ml), due to the failure of diseased renal tissue to respond to the anaemic hypoxic stimulus.
Anaemia usually develops as the GFR falls below 35 ml/min, and worsens with declining GFR.
Other causes of anaemia in renal failure include:
- shortened red blood cell survival;
- uraemic and cytokine inhibition of erythropoiesis (especially infections and inflammatory conditions);
- iron deficiency;
- hypothyroidism;
- active blood loss (including HD circuits, GI bleeding);
- haemolysis;
- haemoglobinopathies;
- aluminium overload;
- hyperparathyroid osteitis fibrosa;
- folic acid or vitamin B12 deficiency.
Anaemia in ESRD is not a trivial problem.
There is a strong association between Hb and risk of death in ESRD.
Increasing Hb causes major improvements in quality of life, exercise capacity, cognitive function, sexual function, immune responsiveness, nutrition, sleep patterns, and improved cardiac status (reduced LVH and dilatation, reduced cardiac output, reduced angina).
Assessment of anaemia and haemolysis
Should be performed when Hb < 13 g/dl (men) or 12 g/dl (women). Initially:
- red blood cell indices;
- blood film;
- white blood cells and platelets;
- reticulocyte count;
- serum iron and total iron binding capacity;
- transferrin saturation;
- serum ferritin (and CRP);
- stool occult blood.
These tests will exclude causes for anaemia other than renal failure itself, especially haemolysis, haematinic deficiency, bone marrow suppression, or infiltration.
Can be caused by:
- contaminants in the dialysate (chloramines—an oxidant—copper, nitrates);
- hypo-osmolar or overheated dialysate;
- re-use sterilants (formaldehyde inducing antibodies);
- blood pump trauma to red blood cells;
- high flows through narrow intravenous catheters or needles;
- drug induced (penicillin, cephalosporin, quinidine, methyldopa);
- causes of microangiopathic haemolytic anaemia or autoimmune haemolysis.
Functional and absolute iron deficiency are important causes of anaemia in ESRD, and especially important causes for failure to respond adequately to EPO.
True iron deficiency is found in up to 40% of patients with ESRD.
However, it is not sufficient for patients with ESRD to have ‘normal’ iron stores. Patients require high iron availability to maximize use of exogenous EPO and maintain satisfactory Hct.
Iron deficiency can be diagnosed by:
- Low serum iron and normal or raised iron binding capacity.
- Low transferrin saturation (<16–20%): marker of amount of iron available for incorporation into Hb. % saturation=serum iron/TIBC×100. Should be maintained >20%.
- Serum ferritin <100 ng/ml: reflects body stores.
- Also an acute phase protein and increased in inflammation or sepsis.
- CRP should be measured at the same time.
- Not entirely reliable marker of mobilizable iron in ESRD but widely available and easily repeatable.
- For patients receiving EPO <150 ng/ml inadequate; 150–400 ng/ml probably inadequate (unless Hb well maintained); 400–1000 ng/ml adequate iron stores; >1000 ng/ml iron overload.
- Increased ferritin is required to restore Hb with increasing anaemia.
- Proportion of hypochromic red blood cells >7–10%.
- A hypochromic red cell has a Hb <28g/dl.
- Normally <2.5% of red cells are hypochromic.
- Histological assessment of bone marrow—rarely performed.
More than 50% of EPO-treated patients remain iron deficient.
Management of anaemia
Erythropoietic agents and intravenous iron are the mainstays of management of the anaemia of renal failure.
There are currently two forms of erythropoietic agents–
- recombinant EPO and
- darbepoietin.
- Recombinant EPO (Epoetin) is available in two forms (α and β), which do not differ in any major way.
- This has been achieved by adding two extra N-linked carbohydrate side-chains to the EPO molecule.
- As a result, Aranesp needs less frequent dosing, usually only once a week or once every 2 weeks, and sometimes only once a month in stable patients.
Erythropoietic agents have been clearly shown to have a beneficial effect in most patients with anaemia of CRF, improving quality of life, exercise capacity, and cognitive function, and reducing LVH and dilatation.
They are beneficial in patients on HD or CAPD, or in those with CRF prior to dialysis.
Their use has removed anaemia as a major cause of morbidity in ESRD, and reduced the need for blood transfusions.
Almost 90% of dialysis patients receive EPO in the US, slightly fewer in Europe.
Response to EPO or darbepoietin varies between individuals, and particularly depends on the dose and route administered, adequacy of iron stores, and concurrent inflammation.
Ideally EPO should be begun when the Hb falls below 11 g/dl (Hct 33%), before LVH begins to develop, although there are no long-term trials yet available comparing timing of initiation.
Economic constraints may prevent early use.
- All dialysis patients with symptoms attributable to anaemia or a Hb <10g/dL (but level controversial, and no good evidence for absolute starting level of Hb).
- Predialysis patients with ESRD and symptomatic anaemia (and may be with a Hb < 10 g/dL—no evidence).
- Treat iron deficiency first.
- EPO is safe and effective in predialysis patients with ESRD.
- It is not associated with increased rate of loss of residual renal function.
- Early use may help prevent cardiac dysfunction associated with anaemia.
Erythropoietin
Administration
- EPO is available as vials containing 1–10000 units per ml, as larger volume multidose vials, as pre-filled syringes with 1–10000 units per syringe, and in the form of a multidose injecting ‘pen’.
- EPO is relatively unstable at room temperature and must be kept in a fridge at 4°C.
- Stability varies somewhat between the main preparations.
- Multidose vials in particular should not be left warm for very long, and pen injectors (containing multidose cartridges) should be carried only for short periods with cooled inserts.
Route of administration
- Subcutaneous administration has historically been shown to allow a 35% (15–50%) reduction in dosing for a given Hb response (compared with intravenous route).
- More recently, however, only a small increase in dose has been needed in patients transferring from the subcutaneous to intravenous routes.
- The subcutaneous route has been the preferred route, until the advent of pure red cell aplasia (PRCA).
- Patients should be taught to self-administer where possible.
- The injection site should be changed at each injection.
- Some patients report stinging with injection probably induced by the citrate buffer in some preparations.
- The presence of benzyl alcohol (as a preservative) in other EPO preparations acts as a local anaesthetic and minimizes stinging.
- Patients usually require doses two to three times each week; daily dosing is no better and should not be used, but weekly dosing may be sufficient in some patients (especially predialysis).
- EPO can also be given intraperitoneally (rarely used), but higher doses are required, and it should ideally be given into a dry abdomen.
- Because of the risk of PRCA (see later) due to the production of anti-EPO antibodies, predominantly with Eprex (the European brand of EPO-α), only EPO-β and darbepoietin are now licensed for subcutaneous administration in Europe.
- Eprex is limited to intravenous use, and is thus restricted to patients on HD.
- Comes in a range of colour-coded pre-filled syringes, ranging from 10–150 µg.
- Should be stored at 2–8°C, in its outer carton to protect it from light, but not frozen.
- May be removed once from storage for a maximum single period of 7 days at room temperature (up to 25°C).
- 1µg darbepoietin is equivalent to 200 IU EPO.
- There is no difference between the IV and the SC doses (unlike EPO).
Initiating therapy
- Patients must have adequate iron stores prior to starting EPO or darbepoietin.
- Serum ferritin should be >200 µg/l and transferrin saturation >20%.
- Oral iron is poorly tolerated and intravenous iron infusions are often needed.
- Iron stores can be depleted rapidly once erythropoiesis is induced.
- Ferritin levels therefore need to be closely monitored and further iron replacement given as needed.
- BP should be well controlled.
- Severe hypertension and fits were a complication of starting EPO when it was first introduced, but are rarely seen with current dosage regimens, with slower rises in Hb levels.
- Starting dose of EPO should be 80–120 units/kg/week (typically 6000 units per week) in two or three divided doses.
- Intravenous doses need to be increased by 30–50% (average 9000 units per week).
- Starting dose of darbepoietin is 0.45 µg/kg weekly either SC or IV.
- If converting patient from EPO to darbepoietin, divide total weekly dose of EPO by 200, and administer IV or SC once a week.
- Target Hb should be reached in 3–4 months (increase in Hb of approx 1 g/dl per month).
- Most patients will require approx 6000–9000 units/week during the maintenance phase, but this is highly variable.
- Hb should be monitored every 2–4 weeks after initiating therapy or after a change in dose.
- If Hb rises too fast, temporarily withhold EPO or darbepoietin.
- Hb should fall about 1 g/dl per month. Reinstate EPO or darbepoietin at a dose approx 25% below previous dose.
- Decrease dose by between 25 and 50% if Hb increases more than 2.5 g/dl in a 4-week period.
- Increase dose of EPO or darbepoietin by approx 25% if increase in Hb < 1g/dl over 4 weeks and iron stores are adequate.
Maintenance therapy
- Hb level should be monitored monthly in HD patients and 2 monthly in predialysis or PD patients.
- If Hb remains at target level, drug dose can be kept unchanged, although dose frequency can be reduced if SC route is being used (keeping total dose unchanged).
- Some patients can be maintained on 2-weekly EPO, or monthly darbepoietin.
- Iron status is crucial to maintaining adequate Hb levels.
- Ferritin and transferrin saturation status should be checked monthly in HD patients and 2 monthly in predialysis and PD patients.
- Regular intravenous iron is needed by many patients.
- Maintenance dose is often 75% of the final dose used during the initial phases of treatment.
- Increased doses may be required during intercurrent illnesses to maintain Hb, but there are no data on the best management strategy.
- Post-transplantation it may take a month for the graft to resume secretion of EPO.
- If given intravenously, EPO should be infused towards the end of dialysis.
- AN69 in particular can adsorb large amounts of EPO.
Side-effects
- Hypertension
- Hypertension is the most common complication (20–50% patients):
- associated with rate of rise in Hb, absolute level of Hb achieved, vasoconstriction induced by treatment, arterial remodelling and enhanced responsiveness to
- noradrenaline;
- hypertensive encephalopathy was seen during the early days of EPO and was associated with a rapid rise in Hb and BP;
- severe hypertension is not seen with slow controlled rise of Hb.
- Hypertension should be managed by fluid removal and appropriate drug treatment.
- EPO and darbepoietin should not be withheld unless evidence of accelerated hypertension.
- Pain at injection site occurs in a few patients using darbepoietin SC; it is much less common with EPO-β.
- Pure red cell aplasia
- This is rare but devastating.
- Caused by formation of antibodies to EPO.
- Very rare and occurred predominantly in patients treated with Eprex (European brand of EPO-α).
- Thought to be due to change in the immunogenicity of the EPO molecule brought about by removing human albumin from solvent (because of risk of prion infection).
- Mostly occurred with SC route of administration, because of increased immunogenicity of proteins when injected SC.
- Diagnosis should be suspected if Hb falls despite increasing dose of EPO—and reticulocyte count is <1% (or <10×109/l), with normal platelet and white cell counts.
- Diagnosis confirmed by finding anti-EPO antibodies in serum, and bone marrow feature of PRCA.
- Various immunosuppression strategies have been used as treatment with some success; Hb will rise, but often reintroduction of EPO (any brand) will re-stimulate production of antibodies. Kidney transplantation can be curative.
- New cases of PRCA now very rare since Eprex only used intravenously.
- No cases have occurred with Aranesp.
Target haemoglobin
- Target Hb remains controversial.
- Tends to be governed by economic factors; there is no randomized clinical trial data yet to support higher Hb levels.
- Current UK Renal Association Hb target is >10.0 g/dl and the European best practice guideline is a target Hb of 11.0 g/dl.
- Patients with angina may get less symptoms at higher Hb levels.
- There is anecdotal evidence that patients with heart failure have less symptoms and improved cardiac function with Hb levels corrected to normal levels.
- Fears about increased vascular access thrombosis with higher Hb levels have not been proven.
- Hb levels in a dialysis population on EPO follow a normal distribution.
- Therefore in order to achieve 80% of patients having a Hb higher than the target, a dialysis unit must aim for a higher Hb level overall.
- To achieve >80% of patients with Hb >11g/dl, it is necessary to aim for a level of 11–12 g/dl (33–36% Hct).
This degree of correction of anaemia improves survival, causes regression of ventricular hypertrophy, improved quality of life, exercise capacity, and cognitive function.
More recently, higher values of Hb have been associated with better cognitive function, better quality of life, further improvement in exercise capacity, and in some patients prevention of progressive left ventricular dilatation.
However, the normal Hct cardiac trial randomized patients with heart disease to normal or usual Hct (and achieved Hct of 42% vs 30%) and was stopped early because of a trend to increased mortality in the normal Hct group.
This result was confounded by a decrease in mortality in both arms with increasing Hct.
The Canadian study of normalization of Hb in HD patients with asymptomatic cardiomyopathy (Hb 11 or 13.5 g/dl) showed improved quality of life with higher Hb, and some cardiac benefits.
Ideal target Hb for maximal benefit therefore remains to be defined.
Failure to respond (resistance)
Most common cause is iron deficiency, often induced by the rise in Hb.
Other causes include:
- inadequate dosing;
- concurrent infection/inflammation;
- compliance;
- hyperparathyroidism;
- bone marrow fibrosis;
- occult malignancy;
- aluminium;
- malnutrition;
- inadequate dialysis;
- haemoglobinopathies;
- other haematinic deficiency;
- other bone marrow disorders, e.g. myelodysplasia;
- PRCA;
- blood loss;
- haemolysis;
- ACE inhibitors;
- carnitine deficiency.
True resistance (to 500–900units EPO/kg/week or 1.5µg/week darbepoietin in iron replete patients) is rare.
- Relative resistance quite common.
Adequate doses of EPO should induce an increase in reticulocytes in the blood.
Iron store should be maintained (ferritin 400–800 ng/ml) with regular iron. Increasing evidence that regular intravenous iron reduces requirements for EPO.
Iron supplements
- All dialysis patients should receive iron unless they have documented excessive iron stores (ferritin >800 ng/ml or transferrin saturation >50%).
- In predialysis patients, iron supplements (oral and/or intravenous) should be given to achieve ferritin >200 ng/ml or transferrin saturation >20%, if Hb <13g/dl in men, or 12 g/dl in women, before starting treatment with erythropoietic agents. Approx 1000 mg iron is needed in the first 3 months of EPO treatment to sustain the increase in Hb, and then approx 25–100 mg/month.
Oral iron
- Comparisons vs placebo have generally shown little benefit in increasing either ferritin or Hb.
- Some patients respond, but many do not.
- Most suffer GI side-effects (proportional to the dose of iron taken).
- 200 mg elemental iron needed a day, taken between meals, and not close to oral phosphate binders.
- Compliance is poor.
- May cause constipation in CAPD patients (to be avoided).
- Slow or delayed release iron more expensive and probably no more efficacious.
- A single study comparing intravenous and oral iron in predialysis patients treated with EPO has shown equivalent effects.
- Efficacious in all studies in increasing Hb, increasing ferritin and transferrin saturation index, and reducing EPO requirements.
- Potential concerns about iron overload, infection, and cardiac dysfunction have not been realized.
- Iron should be withheld if ferritin >800 ng/ml to avoid iron overload.
- Increased risk of infection probably not of great significance, but IV iron should not be given while infection present because of theoretical risk that neutrophil function may be adversely affected.
- Macrocytosis developing during the use of IV iron may reflect the development of folate deficiency.
- Needs go be given with care to avoid adverse reactions:
- Free iron reaction:
- symptoms include hypotension, nausea, vomiting, sweating, back pain, pruritis, and a sudden feeling of being unwell;
- owing to either the effect of iron overload or the result of infusing IV iron too rapidly;
- can be treated if necessary with intravenous hydrocortisone and piriton.
- Anaphylaxis:
- symptoms include laryngeal oedema, erythema, urticaria, palpitations, collapse, loss of consciousness;
- risk very low, but all nurses giving IV iron should be trained in resuscitation, and adrenaline (epinephrine), piriton, hydrocortisone, and resuscitation equipment should be immediately available.
- Three preparations are available:
- iron III hydroxide sucrose complex (also known as iron saccharate),
- sodium ferric gluconate, and
- iron dextran.
- Most regimens using intravenous iron initially aim to correct iron deficiency, and then to maintain iron stores using smaller or less frequent doses.
Iron sucrose
- Widely used in Europe but only licensed in the US in 2000.
- Efficacious with a very low incidence of adverse reactions, and no deaths due to anaphylaxis.
- No need for test dose during first administration.
- Supplied as 100 mg/5 ml single dose vial.
- Usual dosing:
- 100 mg at end of HD on 10 successive dialysis sessions if ferritin <200 ng/ml, then weekly while ferritin <600 ng/ml;
- 200 mg can be given every 1–3 months in CAPD or predialysis patients as an IV infusion.
- Can be given as IV infusion or as slow IV injection (at 20 mg/min).
- Administration protocols:
- 100–200 mg undiluted over 5–10 min (20 mg/min) is recommended;
- 100 mg undiluted over 2 min has been reported as being safe;
- 100 mg in 100 ml N/saline over 15 min.
- Changes in transferrin saturation and ferritin levels can be measured 48 h after IV administration.
Sodium ferric gluconate (Ferrecit)
- Increasingly used.
- Widely available in Europe for decades but recently introduced into the US.
- Non-dialysable, free of dextran polysaccharides.
- Anaphylaxis extremely rare and no deaths have been reported.
- No need of test dose during first administration.
- Mild reactions not uncommon.
- Usually given as 62.5–125 mg IV infusions undiluted over 5–10 min (12.5 mg/min) during consecutive dialysis sessions until 1 g administered, then weekly (while ferritin <600 ng/ml). As with iron sucrose.
- Tolerated by iron dextran sensitive patients.
- Can be given as larger doses to CAPD and predialysis patients (300mg 1–3 monthly, over 90 min) to avoid frequent hospital admissions, or 125 mg in 100 ml N. saline over 60 min.
- Risk of anaphylactic reactions (0.6–1.5%), but probably less commonly than previously reported.
- Can lead to generation of antidextran antibodies (extremely infrequently).
- Because of risk of anaphylaxis, test dose needed for first administration (20 mg diluted in 50 ml saline over 30 min).
- Other adverse effects include itching (1.5%), dyspnoea and wheeze (1.5%), arthralgia, myalgia, fever, headache (often delayed by 24–48 h).
- Dose on each dialysis session initially to treat iron deficiency (usually 20–100 mg, for 10–20 sessions), and then intermittently (usually weekly, fortnightly, or monthly) to maintain iron stores (approx 50–100 mg). Alternatively, 250 mg over half an hour monthly. Give at end of dialysis by slow injection or infusion.
- In CAPD or predialysis patients 500 mg can be diluted into 250 ml saline and given over 30–60 min.
- Total dose iron infusions of specially fractionated iron (III) dextran (20 mg/kg iron over 4–6 h) may avoid the need for repeated infusions.
- Becoming less widely used in view of adverse reactions.
High ferritin and low transferrin saturation index
- Some patients have a high serum ferritin (often <1000 ng/ml) but low transferrin saturation index.
- Further iron can cause iron overload.
- These patients may benefit from intravenous ascorbic acid (300 mg three times per week) to increase Hb and reduce EPO requirements.
- They may also, however, be iron deficient, and respond to further iron.
- CRP is an important indicator that suggests a high ferritin is an inflammatory response.
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