Introduction
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children: 0–13 years
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young people: 14–17 years
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adults: 18 years and over
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Anaemia and CKD
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Anaemia and dialysis
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Blood transfusion and dialysis
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Erythropoietin, EPO, ESA
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ESA Resistance
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Immunosuppression and anaemia
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Immunosuppression and EPO
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Immunosuppression and blood transfusion
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Iron deficiency
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Iron therapy
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Iron toxicity
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Pure red cell aplasia
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Anaemia and dialysis
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Renal anaemia
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Renal transplant and anaemia
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Renal transplant and blood transfusion
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Renal transplant and EPO
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Prospective randomised or quasi-randomised trials
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Controlled trials
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Meta-analysis of several trials
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Cochrane systematic reviews.
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Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines for Management of anaemia in CKD [7],
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Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Anaemia in Chronic Kidney Disease [8]
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The National Institute for Health and Care Excellence (NICE) guidelines (ng8) [3].
Background
Summary of clinical practice guidelines on anaemia of chronic kidney disease
Evaluating and diagnosing Anaemia in CKD (guidelines 1.1–1.5)
Guideline 1.1 – Evaluation of anaemia - screening for anaemia
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at least annually in patients with CKD G3 and
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at least twice a year in patients with CKD G4–5 not on dialysis (2B)
Guideline 1.2 - evaluation of anaemia – Haemoglobin levels
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their haemoglobin (Hb) levels are less than 110 g/L (less than 105 g/L if younger than 2 years) or
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they develop symptoms attributable to anaemia
Guideline 1.3 - evaluation of anaemia - renal function
Guideline 1.4 - evaluation of anaemia - erythropoietin measurement
Guideline 1.5 - Evaluation of anaemia – Baseline investigations
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Serum B12 and serum folate concentrations.
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Tests for haemolysis (plasma/serum levels of haptoglobin, lactate dehydrogenase, bilirubin, Coombs’ test).
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Plasma/serum and/or urine protein electrophoresis.
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Hb electrophoresis.
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Free light chains and bone marrow examination.
Treatment of Anaemia with iron therapy Anaemia of CKD (guidelines 2.1–2.4)
Guideline 2.1 - treatment of Anaemia with iron therapy – Iron repletion
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%HRC <6% / CHr >29 pg/ferritin and TSAT (>100 microgram/L and >20%).
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For children, aim for a target ferritin level greater than 100 microgram/L for CKD patients on dialysis as well as CKD patients not on ESA therapy. (ungraded)
Guideline 2.2 - treatment of Anaemia with iron therapy - initiation of ESA and iron status
Guideline 2.3 - treatment of Anaemia with iron therapy - route of administration
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the availability of venous access
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preferences of the person with anaemia of CKD or, where appropriate, their family or carers
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nursing and administration costs
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cost of local drug supply
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provision of resuscitation facilities
Guideline 2.4 - treatment of Anaemia with iron therapy - upper limit for iron therapy
Treatment with Erythropoiesis stimulating agents (guidelines 3.1–3.11)
Guideline 3.1 - treatment of Anaemia - Erythropoiesis stimulating agents
Guideline 3.2 - treatment of Anaemia - choice of ESA
Guideline 3.3 - treatment of Anaemia with ESA therapy - target Hb
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100 and 120 g/L in adults, young people and children aged 2 years and older (2B)
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95 and 115 g/L in children younger than 2 years of age (reflecting the lower normal range in that age
Guideline 3.4 - treatment of Anaemia without ESA therapy - target Hb
Guideline 3.5 - treatment of Anaemia - initial ESA dose
Guideline 3.6 - treatment of Anaemia with ESA therapy - route of administration
Guideline 3.7 - treatment of Anaemia with ESA therapy - frequency of administration
Guideline 3.8 - treatment of Anaemia with ESA therapy - ESA dose adjustments
Guideline 3.9 - treatment of Anaemia with ESA therapy - ESA dose adjustments
Guideline 3.10 - treatment of Anaemia with ESA therapy
Guideline 3.11 – Caution in prescribing ESA in certain CKD patients sub-group
Monitoring of therapy (guidelines 4.1–4.7)
Guideline 4.1 - monitoring of treatment - Hb during ESA therapy
Guideline 4.2 - monitoring of treatment - iron therapy
Guideline 4.3 - monitoring during intravenous iron administration
Guideline 4.4 - Parenteral iron & infection
Guideline 4.5 - monitoring of treatment - resistance to ESA therapy
Guideline 4.6- evaluation for ESA induced pure red cell Aplasia (PRCA)
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We do not recommend routine screening for anti-erythropoietin antibodies among CKD patients regularly treated with erythropoiesis stimulating agents. (2A)
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We recommend that the diagnosis of ESA induced PRCA should be considered whenever a patient receiving long term ESA therapy (more than 8 weeks) develops all the following (2A):• a sudden decrease in Hb concentration at the rate of 5 to 10 g/L per week OR requirement of transfusions at the rate of approximately 1 to 2 per week,• normal platelet and white cell counts,• absolute reticulocyte count less than 10,000/μl
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We recommend that all ESA therapy should be stopped in patients who develop ESA induced PRCA. (2A)
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We recommend that patients who remain transfusion dependent after withdrawing ESA therapy should be treated with immunosuppressant medications guided by the level of anti EPO antibodies. (2A)
Guideline 4.7 - monitoring of treatment - hypertension during ESA therapy
Anaemia of CKD: Blood transfusion (guidelines 5.1–5.3)
Guideline 5.1 - blood transfusion
Guideline 5.2 - blood transfusion
Guidelines 5.3- blood transfusion
Anaemia of CKD: Post transplant Anaemia (guideline 6.1)
Summary of audit measures on anaemia of chronic kidney disease
Rationale for clinical practice guidelines for anaemia of CKD
Anaemia of CKD (guidelines 1.1–1.6)
Guideline 1.1 – Evaluation of anaemia - screening for anaemia
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at least annually in patients with CKD G3 and
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at least twice a year in patients with CKD G4–5 not on dialysis (2B)
Guideline 1.2 - evaluation of anaemia - Haemoglobin level
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their haemoglobin (Hb) levels are less than 110 g/L (less than 105 g/L if younger than 2 years) or
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they develop symptoms attributable to anaemia
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Men and postmenopausal women Hb < 130 g/L
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Premenopausal women Hb < 120 g/L
Guideline 1.3 - evaluation of anaemia - renal function
Guideline 1.4 - evaluation of anaemia - erythropoietin measurement
Guideline 1.5 - evaluation of anaemia – Baseline investigations
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Serum B12 and folate concentrations.
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Tests for haemolysis (plasma/serum levels of haptoglobin, lactate dehydrogenase, bilirubin, Coombs’ test).
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Plasma/serum and/or urine protein electrophoresis.
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free light chains and bone marrow examination.
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Hb electrophoresis.
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The degree and cause of anaemia,
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Bone marrow responsiveness, and
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Iron stores and iron availability for erythropoiesis.
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The severity of the anaemia is disproportionate to the deficit in renal function,
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There is evidence of iron deficiency,
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There is evidence of haemolysis, or
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There is evidence of bone marrow disorder as manifest by leucopoenia and/or thrombocytopenia.a.)Assessment of anaemia severity
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Macrocytosis could be due to folate or vitamin B12 deficiency.
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In addition to anaemia of CKD, microcytosis could be due to iron deficiency or haemoglobinopathies.
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Macrocytosis with leucopoenia or thrombocytopenia could be due to several factors such as alcohol intake, nutritional deficit (vitamin B12 or folate deficiency), or myelodysplasia.
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Serum folate is more prone to variation and can be affected by the patient’s diet immediately prior to blood being taken, alcohol, trauma and other factors therefore occasionally red cell folate may need to be measured where serum folate is equivocal.
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Haemolysis is suggested by the presence of macrocytosis, high lactate dehydrogenase and positive Coombs test.
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The normal absolute reticulocyte count ranges from 40,000 to 50,000 cells/μL. Although it has a significant inter-patient variability, this test may be useful as a semi-quantitative marker of erythropoietic activity.
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HRC estimation is a useful test for assessment of iron availability but is limited by the effect of sample storage time and need for special analysers. Long sample storage time (> 6 h) may spuriously increase HRC. Because a fresh sample is needed, this measure may not be practical in routine clinical practice.
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If using percentage of hypochromic red blood cells from a fresh sample is not possible, reticulocyte Hb content (CHr) or Ret-Hb could be a suitable alternative.
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If testing for CHr (or Ret-Hb) is not feasible, it is preferable to test ferritin and TSAT together because the combination provides an important insight into erythropoiesis, iron storage and iron availability to bone marrow.
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Low serum ferritin is diagnostic of iron deficiency. High serum ferritin, in addition to expressing the adequacy of iron stores, could be due to inflammatory conditions. TSAT is influenced by nutritional status, timing and inflammation. TSAT is also limited by high day to day variations.
Anaemia of CKD (guidelines 2.1–2.4)
Guideline 2.1 - treatment of Anaemia with iron therapy – Iron repletion
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%HRC <6% / CHr >29 pg / ferritin and TSAT (>100 microgram/L and >20%).
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For Children, aim for a target ferritin level greater than 100 microgram/L for CKD patients on dialysis as well as CKD patients not on ESA Therapy. (ungraded)
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a serum ferritin
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200–500 microgram/L in HD patients,
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100–500 microgram/L in non-HD patients and
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Either <6% hypochromic red cells (HRC), or reticulocyte Hb content >29 pg.
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TSAT > 20%
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Several studies have reported that the dose of ESA required to achieve and maintain a given Hb level is inversely related to iron stores [34‐39]. Iron deficiency (absolute or functional) was the main cause of ESA resistance in the UK but this has now been solved by parenteral iron replacement strategies [40]. The evidence behind the statement that TSAT generally should be maintained at greater than 20% stems from a single RCT comparing higher to lower TSAT targets; patients randomized to a target TSAT of 30% to 50% demonstrated a 40% reduction in ESA dose compared with those assigned to a target of 20% to 30%.
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In a randomised controlled study involving 157 haemodialysis patients comparing iron management based on serum ferritin and transferrin saturation versus CHr, CHr was a markedly more stable analyte than serum ferritin or transferrin saturation. Iron management based on CHr resulted in similar haematocrit and epoetin dosing while significantly reducing IV iron exposure [41].
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In another study involving 164 chronic haemodialysis patients, low CHr (<26 pg) was suggestive of functional iron deficiency. When a subgroup of patients were randomly assigned to receive a single dose of IV iron dextran (1000 mg), A CHr < 26 pg at baseline predicted iron deficiency with a sensitivity of 100% and specificity of 80%. The serum ferritin, transferrin saturation and percentage of hypochromic red blood cells were all less accurate. The time to correction of iron deficiency at the level of the reticulocyte was found to be within 48 h as measured by correction of the mean CHr to >26 pg, and by the shift of the vast majority of the reticulocyte population to CHr > 26 pg within this time span [42].
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In a study comparing TSAT versus CHr as a guide of parenteral iron therapy in 197 Japanese peritoneal dialysis patients, although CHr reflected the iron status more sensitively, TSAT was a better clinical marker for iron supplementation therapy [43]. A cross-sectional study of 72 haemodialysis patients was performed. Mean haemoglobin was 9.6 +/− 0.16 g/dl. Mean haemoglobin content of reticulocytes (CHr) was normally distributed and correlated with MCV, MCH and red cell ferritin. A low CHr identified patients with iron deficiency with normal serum ferritin or transferrin saturation [44].
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Tessitore et al. [45] compared the diagnostic efficiency of different iron markers in chronic haemodialysis patients. Although percentage hypochromia >6% was the best marker to identify responsiveness to intravenous iron; CHr was 78% efficient at cut-off ≤29 pg.
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TSAT and serum ferritin were evaluated in 47 chronic haemodialysis patients with baseline serum ferritin levels <600 ng/ml. Patients were treated with IV dextran (1000 mg over ten haemodialysis treatments). Patients were classified as having iron deficiency if haematocrit value increased by 5% or if their erythropoietin dose decreased by 10% by 2 months. Receiver operator curves demonstrated that none of the iron indices had a high level of utility (both sensitivity and specificity >80%). As such it was concluded that both tests should be interpreted in the context of the patient’s underlying EPO responsiveness. In patients who are responsive to EPO, a transferrin saturation value <18% or serum ferritin level < 100 ng/ml should be used to indicate inadequate iron. When EPO resistance is present, transferrin saturation of <27% or serum ferritin <300 microgram/L should be used to guide iron management [46].
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NICE evaluation of iron therapy in CKD patients suggests that for haemodialysis patients, %HRC > 6 dominated all other iron evaluation strategies (it led both to more QALYs and lower cost). For the other patients, TSAT less than 20% alone or serum ferritin less than 100 micrograms/L alone were the least cost effective strategy, but %HRC was the most cost-effective.
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NICE guidelines on anaemia management in CKD patients suggest to:• Use percentage of hypochromic red blood cells (% HRC; > 6%), but only if processing of blood sample is possible within 6 h. Since a fresh blood sample is needed, this test may be difficult to use routinely in clinical practice.• If using percentage of hypochromic red blood cells is not possible, use reticulocyte Hb content (CHr; < 29 pg) or equivalent tests – for example, reticulocyte Hb equivalent.• If these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 microgram/L).
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If neither test is available, we recommend testing both serum ferritin and transferrin saturation rather than relying on either test separately [46].
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For Children, a target ferritin level greater than 100 microgram/L for CKD patients on dialysis as well as CKD patients not on ESA Therapy is appropriate [47] (ungraded). There is no evidence that a higher ferritin target of 200 microgram/L is beneficial or safe in paediatric CKD HD patients.
Guideline 2.2 - treatment of Anaemia with iron therapy - initiation of ESA and iron status
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For CKD dialysis patients, percentage of hypochromic red blood cells >6%, reticulocyte Hb content <29 pg or are ideal test to assess iron status.
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If these tests are not available or the person has thalassaemia or thalassaemia trait, a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 microgram/L) could be a suitable alternative
Guideline 2.3 - treatment of Anaemia with iron therapy - route of administration
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the availability of venous access
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preferences of the person with anaemia of CKD or, where appropriate, their family or carers
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nursing and administration costs
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cost of local drug supply
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provision of resuscitation facilities
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Proportion of pre-dialysis and PD patients receiving iron therapy; type: oral vs. parenteral
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Proportion of pre-D and PD patients who are iron replete
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proportion of HD who are iron replete
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One randomised study 188 patients of IV iron (1000 mg iron sucrose in divided doses over 14 days) versus oral iron (ferrous sulphate 325 mg TDS) in pre-dialysis patients demonstrated a greater improvement in Hb outcome in those on IV iron (more patients achieved a Hb increased of >10 g/L) but no difference in the proportion of patients who had to commence ESA after the start of the study [48].
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Oral iron is easy and cheap to prescribe. It seems reasonable to treat patients who have not responded to or been intolerant of oral iron with IV iron.
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Two randomised controlled studies of oral versus IV iron supplementation in pre-dialysis patients receiving concomitant ESAs are in agreement. In the first study of 45 patients with Hb <110 g/L given either ferrous sulphate 200 mg TDS versus 300 mg iron sucrose IV monthly, there was no difference in Hb or ESA dose between the oral and IV group receiving ESA over a mean 5.2 months follow-up [51]. Iron stores were greater in the IV than oral group. Five patients (55%) in the oral iron group had diabetes, compared to none on the IV iron group and this may have confounded the results on iron stores. In addition more patients in the oral iron group were exposed to ACEi/ARBs.
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Similar findings were reported in another study of 96 ND-CKD patients comparing 5 weeks of IV iron sucrose (200 mg every 7 days for a total of 5 doses) versus 29 days of thrice daily oral iron (ferrous sulphate 325 mg TDS). There was no difference in Hb or ESA dose but greater increase in ferritin in the IV group [52].In this study the frequency of gastrointestinal symptoms was greater in the oral iron group than the IV iron group (constipation 34.5% vs. 12.5%; nausea 10.4% vs. 4.2%).
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In PD patients a cross-over study of oral and IV iron demonstrated higher Hb and lower ESA doses with IV iron after 4 months oral [53].
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The relative safety of parenteral iron compared with oral iron was assessed in a study involving patients with stage III and IV CKD and iron deficiency anaemia. Patients were randomly assigned to either oral ferrous sulphate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The trial was terminated early based on a higher risk of serious adverse events in the intravenous iron treatment group. There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56–4.04)). Infections resulting in hospitalisation had a significantly increased adjusted incidence rate ratio of 2.12 (1.24–3.64). The authors concluded that among non-dialysis patients with CKD and anaemia, intravenous iron therapy could be associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases [54].
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Conversely; the above finding was not reproduced in another study that involved 626 non dialysis CKD patients with anaemia and iron deficiency not on ESAs. In this study, patients were randomized (1:1:2) to intravenous (IV) ferric carboxymaltose (FCM), targeting a higher (400–600 microgram/L) or lower (100–200 microgram/L) ferritin or oral iron therapy. The primary end point was time to initiation of other anaemia management (ESA, other iron therapy or blood transfusion) or Hb trigger of two consecutive values <100 g/L during Weeks 8–52. The increase in Hb was greater with high-ferritin FCM versus oral iron (P = 0.014) and a greater proportion of patients achieved an Hb increase ≥10 g/L with high-ferritin FCM versus oral iron (HR: 2.04; 95% CI: 1.52–2.72; P < 0.001). Rates of adverse events and serious adverse events were similar in all groups [55].
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Similarly no safety signal could be detected in another study comparing intravenous iron isomaltoside versus oral iron in stage G5 non dialysis patients. In this study 351 iron-deficient patients were randomized 2:1 to either iron isomaltoside 1000 or iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks. Haemoglobin response, serum-ferritin and transferrin saturation were significantly increased with IV iron compared with those treated with oral iron. Incidence of adverse drug reactions was not different between both groups. More patients treated with oral iron sulphate withdrew from the study due to adverse events (4.3 versus 0.9%, P = 0.2) [56].
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At present oral iron should remain first line treatment among CKD patients not on haemodialysis and IV iron used if patients are intolerant of oral iron or remain absolutely or functionally iron deficient despite oral iron. The further interpretation of these results is limited by several factors including the relative short duration of follow-up and limited data on potential long term adverse effects such as the impact of oxidative stress.
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HD patients have additional iron losses from GI bleeding, blood tests and losses in the dialysis lines that result in iron supplementation requirements that outstrip the capacity of the gut to absorb iron. Maintenance IV iron in HD patients greatly reduces ESA requirements and costs [48, 51, 57‐60]. Maintaining iron stores at steady state in a HD population requires 50-60 mg/week of intravenous iron [58]. How this is repleted remains a subject under study. A recent open-label, randomized, multicentre, non-inferiority trial conducted in 351 haemodialysis subjects randomized 2: 1 to either iron isomaltoside 1000 (Group A) or iron sucrose (Group B). Subjects in Group A were equally divided into A1 (500 mg single bolus injection) and A2 (500 mg split dose). Group B were also treated with 500 mg split dose. All treatments showed similar efficacy and safety [61].
Guideline 2.4 - treatment of Anaemia with iron therapy - upper limit for iron therapy
Anaemia of CKD (guidelines 3.1–3.11)
Guideline 3.1 - treatment of Anaemia - Erythropoiesis stimulating agents
Guideline 3.2 - treatment of Anaemia - choice of ESA
Guideline 3.3 - treatment of Anaemia with ESA therapy - target Hb
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100 and 120 g/L in adults, young people and children aged 2 years and older (2B)
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95 and 115 g/L in children younger than 2 years of age (reflecting the lower normal range in that age (2B)
Guideline 3.4 - treatment of Anaemia without ESA therapy - target Hb
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The proportion of CKD stage 4–5 patients with Hb 100–120 g/L.
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The proportion of patients treated with an ESA with Hb > 120 g/L.
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Mean (median) ESA dose in patients maintained on ESA therapy.
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In determining target Hb guidelines it is important to assess potential benefits (in terms of possible improved survival, improvement in health related quality of life (HRQoL) and avoidance of transfusion requirement and hospitalisation) vs. potential harms (increased mortality, increased risk of vascular events).
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Although several studies have shown that higher Hb targets could be associated with improvements in both physical and mental health domains [67], the HRQoL benefits of higher Hb targets diminish over time [67]. In addition, there is no apparent Hb threshold above which there is definitively a quality-of-life improvement in the higher Hb treatment arms.
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Besarab et al. [68] reported a study of normalisation of haemoglobin in 1233 prevalent CKD G5HD patients with high cardiovascular risk on haemodialysis. Normalisation of haemoglobin showed no benefit in risk reduction but did show an improvement in quality of life. The treatment arm showed a trend towards increased risk of death failure (183 deaths and 19 myocardial infarcts, producing 202 primary events, compared to 164 events (150 deaths, 14 myocardial infarcts) and vascular access (39% versus 29%) and the trial was terminated before completion on the grounds that the study was unlikely to show benefit from normalisation.
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Two studies evaluated the effect of ESA on patients not yet on dialysis – CHOIR [69] and CREATE [70]. The outcome of the CHOIR study showed no benefit of higher Hb outcome in CKD patients (GFR 15-50 ml/min) randomised to Hb of 113 g/L vs. 135 g/L. Higher outcome target Hb had an increased risk (using composite end-points of death, myocardial infarction, or hospitalisation for congestive cardiac failure) and no incremental improvement in quality of life [69]. The limitation of this study is that, compared with the group assigned to the lower Hb treatment target, the higher Hb target group showed at baseline a statistically greater proportion of patients with a history of hypertension and coronary artery bypass graft. A report posted by the study sponsor [71] indicates that patients assigned to the higher Hb treatment arm also had a significantly greater severity of congestive heart failure (CHF) at baseline. The results of a multivariate analysis, included in this report, indicate that after adjustment for baseline conditions (CHF by National Health and Nutrition Examination Survey CHF score, atrial fibrillation/flutter, serum albumin level, reticulocyte count, and age), the relationship between treatment assignment and primary composite outcome events is no longer statistically significant (HR, 1.24; 95% confidence interval [CI], 0.95 to 1.62; p = 0.11 compared with the unadjusted HR of 1.34; 95% CI, 1.03 to 1.74; p = 0.03) [72]. A secondary analysis of the CHOIR trial suggested that higher doses of epoetin α, rather than target Hb per se, were associated with an increased risk of death, myocardial infarction, congestive heart failure or stroke compared with lower epoetin doses, and with poorer outcomes [72]. Another secondary analysis of the CHOIR study found that, among patients with diabetes mellitus, the percentage of patients reaching the primary end point of death, myocardial infarction, congestive heart failure or stroke within 3 years was similar in the high and low haemoglobin arms of the trial (24.8% versus 24.7%, respectively; p = 0.249). By contrast, among patients without diabetes mellitus at baseline, 36.4% of patients randomized to the higher Hb target had reached the primary end point after 3 years compared with 24% of those randomized to the lower haemoglobin target (HR 1.70; 95% CI 1.03–2.81; p = 0.04). Individuals without diabetes mellitus randomized to the higher haemoglobin target had a significantly greater risk of reaching the primary end point after 3 years than individuals with diabetes mellitus randomized to the lower haemoglobin target [73].
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The CREATE [70] study reported that early correction of anaemia to normal Hb (130-150 g/L vs. 105-115 g/L) did not reduce risk of cardiovascular events. Indeed the hazards ratio for primary endpoints of death from any cause or death from cardiovascular disease consistently (but not significantly) favoured the lower haemoglobin target group. The trend to increase in events appeared to occur after initiation of dialysis but there was no difference in endpoints after censoring of data from patients who started dialysis. Quality of life was significantly better in the higher Hb outcome group. Although GFR was not significantly different between the two groups, more patients started renal replacement therapy earlier in the higher Hb outcome group (p = 0.03) with the difference apparent from 18 months. An important limitation of this trial is that the event rate was much lower than predicted; thus, the power to detect a difference in event rates was decreased [70].
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Other important limitation (s) of these trials is that important subgroups of patients enrolled in large trials, such as young adults, patients returning to dialysis after failed renal transplant, or patients with chronic lung disease were not identified or assessed in any of these trials.
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Further analysis of outcome of high target Hb was performed by the KDOQI team [74]. An Evidence Review Team analysed all data from randomized controlled trials of anaemia management in CKD, including, CHOIR, CREATE and other studies. Combining mortality outcomes from eight studies involving 3038 subjects with CKD who were not on dialysis (the CHOIR and CREATE studies contributed most of the weight to the analysis) revealed no difference between the higher and lower Hb target [73], but combining adverse cardiovascular events from six studies involving 2850 subjects showed an increased risk among the patients assigned to the higher Hb targets (a RR of 1.24, 95% CI 1.02–1.51) [74], although it is worth noting that the CHOIR and CREATE studies also contributed most of the weight to the analysis. Among dialysis patients, combining mortality (four studies, 2391 subjects) or cardiovascular outcomes (three studies, 1975 subjects) showed no statistically significant difference between the higher and lower Hb level with The US Normal Haematocrit Study [68] contributing most of the weight to the analysis.In the TREAT study [75], 4038 patients with diabetes, chronic kidney disease not on dialysis, and anaemia, were randomly assigned in a 1:1 ratio to darbepoetin α, to achieve Hb level of approximately 130 g/L or to placebo, with rescue darbepoetin α when the haemoglobin level was less than 90 g/L. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. After a median follow up of 29 months, there was no difference between the two arms in the primary outcome of death, cardiovascular event or end stage renal disease. Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin α and 53 patients assigned to placebo (HR, 1.92; 95% CI, 1.38 to 2.68; p < 0.001). The investigators concluded that for many involved in clinical decision making this risk of prescribing an ESA in this patient population will outweigh the potential benefits [75].
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Data from observational studies have, however, not shown increased hazard risk among patients who achieved higher Hb. In one study, data from haemodialysis patients in the UK Renal Registry from 1999 to 2005 were analysed for the relative risk of death at different Hb concentrations. Hb concentrations above the reference range (100–110 g/L) consistently showed a 35% lower relative risk of death, while patients with haemoglobin below 100 g/L had a 28% higher mortality. The greatest mortality was seen in patients with haemoglobin <90 g/L (73% increased risk of death, although due to the small numbers, this was not statistically significant). On the other hand, the lowest death rate was seen in patients with haemoglobin levels between 120 and 139 g/L (64% reduced mortality) [76].
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The effect of cumulative ESA dose was also reported in another retrospective study [77]. In this study, which looked at data from Medicare’s end-stage renal disease program between 1999 and 2007, different US dialysis centres annual anaemia management practice were characterised by estimating their typical use of ESAs and intravenous iron in haemodialysis patients within 4 hematocrit categories. Monthly mortality rates were assessed using Cox proportional hazards regression to correlate centre-level patterns of ESA and iron use with 1-year mortality risk in 269,717 incident haemodialysis patients. Monthly mortality rates were highest in patients with haematocrit less than 30% (mortality, 2.1%) and lowest for those with haematocrit of 36% or higher (mortality, 0.7%). After adjustment for baseline case-mix differences, dialysis centres that used larger ESA doses in patients with haematocrit less than 30% had lower mortality rates than centres that used smaller doses (highest vs. lowest dose group: HR, 0.94; 95% CI, 0.90–0.97). Centres that administered iron more frequently to patients with haematocrit less than 33% also had lower mortality rates (highest vs. lowest quintile, HR, 0.95; 95% CI, 0.91–0.98). However, centres that used larger ESA doses in patients with haematocrit between 33% and 35.9% had higher mortality rates (highest vs. lowest quintile, HR, 1.07; 95% CI, 1.03–1.12). More intensive use of both ESAs and iron was associated with increased mortality risk in patients with haematocrit of 36% or higher [77].
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The findings of all the above studies have obviously made it difficult to define a safe target Hb in CKD patients treated with ESA. As a result Target Hb in this patient group has been the subject of extensive debate in the literature:• KDIGO suggest that for adult CKD patients on dialysis, ESA therapy could be used to avoid having the Hb concentration fall below 90 g/l by starting ESA therapy when the haemoglobin is between 90 and 100 g/L.• The Anaemia Working Group of ERBP expressed its view that Hb values of 110–120 g/L should be generally sought in the CKD population without intentionally exceeding 130 g/L In low-risk patients (i.e. in younger patients with very few comorbidities). In those with ischaemic heart disease with worsening ischaemic symptoms associated with anaemia, or in those in whom a clear benefit on quality of life can be foreseen, the start of ESA therapy could be considered at higher Hb values but not exceeding 120 g/L. In high-risk patients, including those with asymptomatic ischaemic heart disease, treatment initiation with ESA should be started at Hb values between 90 and 100 g/ L in order to maintain a Hb value ∼100 g/L during maintenance therapy [78].• NICE guidelines on managing anaemia in CKD patients suggest maintaining the “aspirational” Hb range between 100 and 120 g/L for adults. The rationale behind choosing a wide target Hb range (100–120 g/L) for this guideline is that when the target Hb level is narrow (i.e.10 g/L), variability in achieved Hb levels around the target is high, the fraction of prevalent patients with achieved Hb levels within the target range is low and ESA dose titration is required frequently during maintenance therapy.• The health economics of anaemia therapy using ESAs has been subject to a NICE systematic review which concludes that treating to a target Hb 100-120 g/L is cost effective in HD patients. Table 1 summarises the mean Hb data for prevalent UK dialysis patients from the Thirteenth (2010) and Seventeenth (2013) UK Renal Registry Reports.Table 1Hb data for UK prevalent HD patients [79]Median HbHb > 100 g/LHb 100–120 g/LInterquartile Hb rangeHb >110 g/L and not on ESA2010115 g/L85%53%105–123 g/L10%2013112 g/L83%59%103–120 g/L11%• The Medicines and Healthcare products Regulatory Agency (MHRA) guidance (2007) notes that using ESAs to achieve Hb levels greater than 120 g/L is associated with an increased risk of death and serious cardiovascular events in people with CKD. The MHRA advises that Hb levels greater than this should be avoided, and that patients should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of the symptoms of anaemia. Use of ESAs to achieve Hb levels greater than 120 g/L is not consistent with UK marketing authorisations for ESAs. Informed consent should be obtained and documented [80].
Guideline 3.5 - treatment of Anaemia - initial ESA dose
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Type(s) of licensed ESAs available
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Initial ESA dose
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ESA dose adjustment: dose required for Hb correction vs. maintenance
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Route of ESA administration
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Frequency of ESA administration that best fit patient requirements and achieve maximal convenience
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Patient monitoring for the anticipated response in terms of Hb rise, rate of Hb rise, possible adverse effect (e.g. hypertension).
Guideline 3.6 - treatment of Anaemia with ESA therapy - route of administration
Guideline 3.7 - treatment of Anaemia with ESA therapy - frequency of administration
Guideline 3.8 - treatment of Anaemia with ESA therapy - ESA dose adjustments
Guideline 3.9 - treatment of Anaemia with ESA therapy - ESA dose adjustments
Guideline 3.10 - treatment of Anaemia with ESA therapy
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The NICE Guidelines for anaemia management in chronic kidney disease recommend an “aspirational” Hb of 100–120 g/L. It is anticipated that if a population Hb distribution is centred on this outcome with a mean of 110 g/L, then 85% of the population will have Hb > 100 g/L.
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In HD patients, withholding ESA doses for Hb levels greater than the target range is associated with subsequent downward Hb excursions often to levels less than target Range [91]. The time between withholding ESA doses and return of Hb to target range is variable and unpredictable. In HD patients with Hb values greater than 140 g/L, the median time for Hb to return to 120 g/L or less after withholding of a SC-administered ESA is 7–9 weeks. The difference between withholding long and short acting ESAs on the rate of Hb reduction is not significant.
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ESA dose adjustment may be higher during initiation (or titration after switch between different ESAs) than maintenance phases of ESA therapy. In a randomized double blind trial comparing a short-acting ESA with a long-acting ESA in haemodialysis patients previously receiving epoetin α, dose adjustments were made in 25% increments or decrements of the baseline dose, aiming to maintain individual Hb concentrations within a range of 90 to 130 g/L [92]. Approximately 70% of patients required dose adjustment in the 20-week titration period, and 50% required dose adjustment during the 8 week maintenance period.
Guideline 3.11 – Caution in prescribing ESA in certain CKD patients sub-group
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In the TREAT study, there was an increased risk of stroke in the high ESA group (HR 1.92; 95% CI 1.38–2.68): 5.0% of the high Hb group had a stroke compared to 2.6% in the placebo group (P < 0.001). Venous thrombo-embolic events occurred significantly more frequently in the high Hb arm (2.0%) compared to the placebo arm (1.1%, P = 0.02).
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A post-hoc analysis of TREAT study showed that: 7.4% of those with a history of malignancy at baseline died from cancer in the ESA arm compared to 0.6% in the placebo arm (P = 0.002) [93].
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Patients with neoplasia who received ESA in randomised clinical trials had an increased risk of tumour progression and reduced overall survival compared with study controls [96].
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The MHRA advised that r-HuEPOs should not be given to patients with cancer who do not fulfil the criteria in the authorised cancer indications, and that patients should be monitored closely to ensure that the lowest approved dose of r-HuEPO is used to adequately control of symptoms of anaemia [96].
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The joint guideline from the American Society of Clinical Oncology and the American Society of Haematology [97] recommend using ESA therapy with great caution in patients with active malignancy, particularly when cure is the anticipated outcome.
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NICE evaluated the efficacy and safety of ESA in treating anaemia in cancer patients receiving chemotherapy [98]. Although NICE researchers identified 23 randomised controlled trials evaluating the effectiveness and safety of erythropoiesis-stimulating agents (ESAs) for treating cancer treatment-related anaemia. NICE assessment focused only on trials that evaluated ESAs at a starting dose reflecting the current licence (Hb <100 g/L). In total 16 studies were included in the analysis of the outcome related to anaemia and 7 trials in the outcome related to overall survival. NICE analysis of available trials concluded that erythropoiesis-stimulating agents are recommended, within their marketing authorisations, as options for treating anaemia in people with cancer who are having chemotherapy. ESAs were effective in increasing haemoglobin concentrations, improving haematological responses, reducing the need for blood transfusions and improving health-related quality of life, but that it could not assume that ESA treatment either prolonged or shortened survival compared with treatment without an ESA [98].
Anaemia of CKD (guidelines 4.1–4.5)
Guideline 4.1 - monitoring of treatment - Hb during ESA therapy
Guideline 4.2 - monitoring of treatment - iron therapy
Guideline 4.3 - monitoring during intravenous iron administration
Guideline 4.4- Parenteral iron & infection
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Parenteral iron administration to haemodialysis patients has been shown to result in a reduction of circulating TNFα levels [109]. In addition, chronic iron loading has been associated with an impaired immune response of circulating monocytes to ex vivo stimulation with LPS [110]. Excess iron inhibits anti-microbial effector pathways of macrophages [110, 111]. This is exerted via blockade of LPS and interferon-gamma (IFNJ) inducible immune pathways, while production of macrophage de-activating cytokines such as interleukin-10 (IL10) is increased [112, 113]. The effect of iron on immune function could be dependent on the iron preparation; one study have shown that iron sucrose had more prominent effects on monocyte differentiation than other clinically available compounds [114].
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Ishida and Johansen critically reviewed available literature regarding the association between iron and infection in HD patients [115]. The authors identified studies that evaluated the association between the risk of infection, serum ferritin levels (13 studies) and iron usage (24 studies). Thirteen studies with sample sizes ranging from 61 to 2662 have examined the link between serum ferritin and infection in haemodialysis patients. Among the 13 studies, nine studies reported an association and four studies did not find an association between serum ferritin and infection. Among the studies that identified an association, high serum ferritin (typically defined as >500 or 1000 microgram/L) was associated with higher incidence of bacterial infection or infection-related mortality. The incidence of bacterial infection ranged from 0.34 to 0.59 infections per patient-year (in studies evaluating the rate of infection) and 0.93% to 61.9% (in studies evaluating the proportion with infection) in the higher serum ferritin groups and 0.09 to 0.18 infections per patient-year and 0% to 37% in the lower serum ferritin groups. The authors concluded that these studies suggest an excess of 16 to 50 infections per 100 patient-years in the higher compared with the lower serum ferritin groups. In studies that expressed the association between serum ferritin and bacterial infection as ratios, higher serum ferritin was independently associated with a 1.5 to 3.1-fold higher incidence of bacterial infection or infection-related mortality. Among the 24 studies that evaluated the relationship between iron therapy and infection, 22 studies were observational with sample sizes ranging from 21 to 309,219 patients. Twelve of these studies found an association between any iron usage, higher dose or frequency of iron usage and infection or infection-related mortality.
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One study compared mortality with different dosing patterns of IV iron [116]. Based on data from 117,050 HD patients, the study evaluated the effect of bolus versus maintenance IV iron dosing during repeated 1-month exposure periods on risks of mortality and infection-related hospitalization during the subsequent 3 months. In multivariable additive risk models, compared to maintenance dosing (median monthly dose 200 mg), bolus dosing (median 700 mg) was associated with an increased risk of infection-related hospitalization (risk difference, 25 additional events/1000 patient-years; 95% CI, 16 to 33), with the risk being largest among patients with a catheter or history of recent infection. An association between bolus dosing and infection-related mortality was also observed. In contrast, maintenance and low-dose iron (125 mg) dosing were not associated with increased risks of infection-related hospitalization or mortality outcomes when compared with no iron.
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A multicentre study prospectively evaluated the association between serum ferritin levels and IV iron usage with adverse outcomes and mortality among 1086 Japanese chronic HD patients. By using Cox proportional hazard models and time-dependent variables, there was a significantly higher risk of infection with higher (above 100 microgram/L) compared to lower (below 100 ng/dl) serum ferritin levels, and with high (≥50 mg/week) and even low (<50 mg/week) doses of IV iron compared with no IV iron; they also reported significantly higher risk of death among patients with high-amplitude ferritin fluctuations (serum ferritin level consistently above 100 microgram/L or upward trend from below to above 100 microgram/L) compared with those with low ferritin level [117].
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In a study involving 626 patients with pre-dialysis CKD patients. Patients were treated with intravenous ferric carboxymaltose (with a high and low ferritin target) or oral iron for 52 weeks. The percentage of deaths, myocardial infarctions, and infections was not significantly different between oral iron–treated and IVI-treated patients. However, the study was not powered to evaluate safety of parenteral iron.
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In a study evaluating the safety of parenteral iron therapy in10,169 haemodialysis patients in the United States; after adjusting for 23 demographic and comorbidity characteristics among 5833 patients included in the multivariable analysis; bills for ≤10 vials of iron over 6 months showed no adverse effect on survival when compared with none, but bills for >10 vials showed a statistically significant elevated rate of death. Bills for ≤10 vials of iron over 6 months also showed no significant association with hospitalization (adjusted = 0.92; 95% CI, 0.83 to 1.03; P = 0.15), but bills for >10 vials showed statistically significant elevated risk. More intensive dosing was associated with diminished survival and higher rates of hospitalization, even after extensive adjustment for baseline comorbidity. [118]
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A subsequent analysis of 32,566 Fresenius Inc. haemodialysis patients by the same authors did not confirm an association between IVI dose and risk of death after adjusting for time-varying measures of iron treatment and fixed and time-varying measures of morbidity [119]
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Kalantar-Zadeh et al. studied 58,058 DaVita Inc. dialysis patients. For patients who received 400 mg of IVI per month, the risk for death was found to be lower compared with patients with no IVI administered. By contrast, doses >400 mg per month were associated with increased risks of death [120].
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Kshirsagar et al. studied 117,050 haemodialysis patients. No association was found between dose of IVI and short-term risk of myocardial infarction, stroke, or death [121].
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A prospective observational study by Hoen et al. followed 988 haemodialysis patients from 19 French centres for 6 months. There were 51 episodes of bacteraemia, but no association with either IVI dosing or serum ferritin concentration was detected [122]A more recent study from the same group in 985 dialysis patients, demonstrated no increase in infection rates [123].