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María José Navarro
María del Carmen de Gracia
María de los Ángeles García
Department of Nephrology
Santa María del Rosell Hospital
Patients with chronic kidney disease frequently suffer from anaemia, typically when renal function falls below a glomerular filtration rate of 30ml/min. Approximately 80% of patients on dialysis experience this condition. Although anaemia can significantly affect morbidity, mortality and quality of life in these patients, less than one-third of predialysis patients receive treatment with an erythropoietic stimulating factor.(1) There is a real need for anaemia management. First, in patients with severe anaemia (haematocrit <27%), mortality is 60% higher than in patients with moderate anaemia (31–33%).(2) Secondly, prospective epidemiological evidence shows that earlier treatment reduces mortality during the first year of dialysis.(3) Renal anaemia is caused by the inadequate production of erythropoietin by chronically diseased kidneys; this is the main but not the only factor, as uraemic anaemia is obviously multifactorial in origin (extracorporeal haemolytic component, iron deficiency, loss of folate, etc).
On the basis of available evidence, the European Best Practice Guideline 1 for the management of anaemia in patients with chronic renal failure(4) proposes that haemoglobin (Hb) values in individuals living below an altitude of 1,500m are considered below normal if they are <11.5g/dl in women, <13.5g/dl in adult men younger than 70 years and <12g/dl in men above the age of 70. Diagnosis of anaemia must be made when haemoglobin concentrations fall below these levels. Thus, an initial clinical and laboratory evaluation to assess the degree of anaemia (Hb concentration), the type of anaemia (red blood cell indices), erythropoietic activity (reticulocyte count), iron stores and functional iron available for the erythropoiesis (serum ferritin concentration, serum transferrin saturation and percentage of hypochromic red blood cells), inflammation (serum C-reactive protein) and dialysis dose (Kt/V) must be carried out. Aluminium, intact parathyroid hormone, B12 and folate concentrations should be measured. Finally, as gastrointestinal bleeding is common in patients with chronic renal failure, an assessment of occult gastrointestinal bleeding should be carried out.
Management of anaemia
Iron and erythropoietic stimulating agents (ESAs) are essential in anaemia treatment in dialysis patients, but what are the appropriate Hb and iron targets? In general, dialysis patients should maintain (or reach as soon as possible) a target Hb concentration of >11g/dl, regardless of age, gender or ethnicity. Optimal target Hb concentrations must be defined for individual patients, taking epidemiological factors, activity and comorbid conditions into account. To reach and maintain target Hb concentrations in patients undergoing treatment with an ESA, sufficient iron should be administered to obtain a serum ferritin concentration >100µg/l and hypochromic red cells <10% (or transferrin saturation >20%).
ESAs must be given to all dialysis patients with haemoglobin levels <11g/dl and other causes of anaemia excluded. Recombinant human erythropoietin has been available for more than a decade (epoetin alfa and beta), with darbepoetin alfa arriving on the market in the last few years. Epoetin beta and darbepoetin alfa can be given either intravenously or subcutaneously. Epoetin alfa is not licensed for subcutaneous administration in all Member States of the European Union, due to the risk of pure red cell aplasia.
In patients treated with peritoneal dialysis or predialysis and in transplant patients, subcutaneous administration is elective. The intravenous route is preferred for haemodialysis patients. The frequency of administration in patients receiving epoetin is two or three times a week. During the correction phase, darbepoetin must be given once a week; it can be even less often during the maintenance phase (once every 2–4 weeks).
Treatment with darbepoetin alfa not only reduces the frequency of dose administration, but also allows dose reduction. Studies carried out in our team demonstrated that darbepoetin administered either subcutaneously or intravenously once a week or every other week is more effective than epoetin and significantly improves the resistance index (defined as weekly dose per kilogram of weight/levels of Hb).(5,6) It results in a dose reduction of 15–30%. According to these and other published results,(7,8) darbepoetin alfa must be considered as the treatment of choice for anaemia treatment in dialysis patients.
Patients receiving ESA treatment may require frequent monitoring of Hb concentrations both in correction (once every 2–4 weeks) and in maintenance (once every 1–2 months) phases because the dose of ESA administered must be titrated in response to Hb levels.
Intravenous administration is the optimum route for the delivery of iron to patients with chronic kidney disease, particularly those on dialysis and those receiving ESA therapy, as oral iron is poorly absorbed in uraemic individuals. However, for practical reasons, oral iron can be considered for patients on peritoneal dialysis. Iron sucrose is the safest form of intravenously administered iron, and no definitive recommendation can be made regarding the optimum administration frequency. Giving 100–200mg of iron intravenously at weekly or even monthly intervals is a common practice in our dialysis unit. Although there is little evidence on the optimal frequency for the monitoring of iron status, most studies describe monthly tests of iron indices.
Treatment with vitamin E, correction of impaired vitamin C status, folic acid and vitamin B12 supplementation or treatment with l-carnitine are forms of therapy that may help to optimise a patient’s response to treatment with ESAs.
Finally, dialysis should be optimised to ensure the effective treatment of renal anaemia. Alternative dialysis treatment,(9,10) such as enhanced convective treatment (haemodiafiltration online) or daily dialysis, can also improve the outcome in haemodialysis patients.
Unfortunately, a considerable percentage of patients are below the target Hb level of 11g/dl. The most common causes of resistance or hyporesponsiveness to ESAs are iron deficiency, either absolute or functional, and inflammation. However, other conditions, such as chronic blood loss, hyperpara‑thyroidism, malnutrition or malignancies, must also be checked.
Most dialysis patients can be treated with ESAs and iron supplementation, and Hb concentrations often improve, as do, consequently, signs and symptoms related to renal anaemia.