Discover Portal

Administering medicine through injection

NIHR Signal Iron deficiency in people with chronic kidney disease can be managed with either oral or IV therapy

Published on 4 June 2019

doi: 10.3310/signal-000773

For people with chronic kidney disease who are also iron deficient, intravenous iron improves haemoglobin levels and iron stores faster than oral iron. However, the evidence is inconclusive about whether it influences survival, cardiovascular death, or quality of life. Adverse effects and such as allergic reactions or gastrointestinal side effects and other practicalities are likely to determine the choice of a route of administration.

Chronic kidney disease is a long-term condition categorised into five stages as the kidneys progressively lose function. Anaemia is common and can be made worse by iron deficiency. When levels are low, there is uncertainty about which form of iron therapy brings greatest benefit.

This Cochrane review update included 39 trials comparing intravenous to oral iron therapy in both adults and children with chronic kidney disease.

The findings support existing NICE guidance regarding the choice of route for iron therapy for people with CKD.

Share your views on the research.

Why was this study needed?

Around three million people have chronic kidney disease in the UK, and about 61,000 of these have kidney failure (stage 5 disease).

Anaemia is twice as likely for people with chronic kidney disease as the general population, and for those with kidney failure over half will be anaemic. Chronic kidney disease impairs production of red blood cells, and the problem is often exacerbated by iron deficiency.

This review update adds a further 11 studies to the previous review from 2012. The researchers aimed to assess potential benefits and harms of intravenous and oral iron therapy for people with chronic kidney disease. This update brings an increased focus on patient-centred outcomes such as quality of life.

What did this study do?

In this systematic review, researchers looked at 39 randomised and quasi-randomised controlled trials (3,852 participants). These trials compared intravenous and oral iron therapy in adults and children with stages 3 to 5 disease, including some trials with patients on haemodialysis. There was considerable variation in the formulations and doses of intravenous and oral iron preparations used. Follow up lasted from 35 days to 26 months.

The review’s primary outcomes were death from any cause, cardiovascular death, and quality of life.

Certainty around these outcomes is limited by the quality of included studies, short durations of treatment and follow-up, and the lack of inclusion of patient-centred outcome measures in many of the studies.

What did it find?

  • Deaths from all causes during the trial periods were not found to be different, between patients given intravenous (3.3%) and oral iron therapy (3.1%) (risk ratio [RR] 1.12, 95% confidence interval [CI] 0.64 to 1.94;).
  • Cardiovascular deaths during the trial periods were not found to be different between intravenous (3.4%) and oral iron therapy (2.0%) groups (RR 1.71, 95% CI 0.41 to 7.18).
  • Quality of life was not found to be different between the two groups.
  • Target haemoglobin levels were more likely to be achieved by people receiving intravenous (54%) than oral iron therapy (32%) (RR 1.71, 95% CI 1.43 to 2.04).
  • Allergic reactions or low blood pressure were three times as likely in those receiving intravenous (2.4%) than oral iron therapy (0.7%) (RR 3.56, 95% CI 1.88 to 6.74).
  • Gastrointestinal adverse effects were less common with intravenous than oral iron therapy, particularly constipation which was one third as likely, occurring in 3% compared with 11% on oral iron (RR 0.32, 95% CI 0.18 to 0.57).

What does current guidance say on this issue?

The NICE 2015 guideline and 2017 treatment pathway recommend that for anaemic patients with chronic kidney disease, iron therapy should be offered before erythropoietic stimulating agents are considered for treating anaemia.

The guidelines recommend taking account of patient choice following discussion or the risks and benefits of treatment options. Generally, for people not receiving haemodialysis oral iron should be the first line therapy, with intravenous therapy offered if this is not tolerated or target haemoglobin levels are not reached within three months. For people who are receiving haemodialysis, intravenous iron should be the first line therapy.

What are the implications?

This review found no evidence of a difference in patient-centred outcomes between people with chronic kidney disease receiving intravenous or oral iron therapy. Doubts remain over the relative benefits for patients in terms of overall deaths, deaths caused by heart disease and quality of life.

There were greater improvements in haemoglobin levels and laboratory iron markers when using intravenous iron. Intravenous iron therapy led to more allergic reactions but fewer gastrointestinal side effects than oral therapy.

The findings are in keeping with existing NICE guidance. An approach balancing risks of adverse effects and the practicalities of delivering intravenous and oral iron therapy continues to be appropriate.

Citation and Funding

O'Lone E. L., Hodson E.M., Nistor, I et al. Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database Syst Rev. 2019;(2):CD007857.

No external funding sources were reported.

Bibliography

NICE. Chronic kidney disease: managing anaemia. NG8. London: National Institute for Health and Care Excellence; 2015.

NICE Pathways. Managing anaemia in people with chronic kidney disease. London: National Institute for Health and Care Excellence; 2017.

NHS Choices. Chronic Kidney Disease. London: NHS England; 2016.

Kidney Care UK. Anaemia. Alton: Kidney Care UK; 2019.

Kidney Care UK. Facts and Stats. Alton: Kidney Care UK; 2019.

Why was this study needed?

Around three million people have chronic kidney disease in the UK, and about 61,000 of these have kidney failure (stage 5 disease).

Anaemia is twice as likely for people with chronic kidney disease as the general population, and for those with kidney failure over half will be anaemic. Chronic kidney disease impairs production of red blood cells, and the problem is often exacerbated by iron deficiency.

This review update adds a further 11 studies to the previous review from 2012. The researchers aimed to assess potential benefits and harms of intravenous and oral iron therapy for people with chronic kidney disease. This update brings an increased focus on patient-centred outcomes such as quality of life.

What did this study do?

In this systematic review, researchers looked at 39 randomised and quasi-randomised controlled trials (3,852 participants). These trials compared intravenous and oral iron therapy in adults and children with stages 3 to 5 disease, including some trials with patients on haemodialysis. There was considerable variation in the formulations and doses of intravenous and oral iron preparations used. Follow up lasted from 35 days to 26 months.

The review’s primary outcomes were death from any cause, cardiovascular death, and quality of life.

Certainty around these outcomes is limited by the quality of included studies, short durations of treatment and follow-up, and the lack of inclusion of patient-centred outcome measures in many of the studies.

What did it find?

  • Deaths from all causes during the trial periods were not found to be different, between patients given intravenous (3.3%) and oral iron therapy (3.1%) (risk ratio [RR] 1.12, 95% confidence interval [CI] 0.64 to 1.94;).
  • Cardiovascular deaths during the trial periods were not found to be different between intravenous (3.4%) and oral iron therapy (2.0%) groups (RR 1.71, 95% CI 0.41 to 7.18).
  • Quality of life was not found to be different between the two groups.
  • Target haemoglobin levels were more likely to be achieved by people receiving intravenous (54%) than oral iron therapy (32%) (RR 1.71, 95% CI 1.43 to 2.04).
  • Allergic reactions or low blood pressure were three times as likely in those receiving intravenous (2.4%) than oral iron therapy (0.7%) (RR 3.56, 95% CI 1.88 to 6.74).
  • Gastrointestinal adverse effects were less common with intravenous than oral iron therapy, particularly constipation which was one third as likely, occurring in 3% compared with 11% on oral iron (RR 0.32, 95% CI 0.18 to 0.57).

What does current guidance say on this issue?

The NICE 2015 guideline and 2017 treatment pathway recommend that for anaemic patients with chronic kidney disease, iron therapy should be offered before erythropoietic stimulating agents are considered for treating anaemia.

The guidelines recommend taking account of patient choice following discussion or the risks and benefits of treatment options. Generally, for people not receiving haemodialysis oral iron should be the first line therapy, with intravenous therapy offered if this is not tolerated or target haemoglobin levels are not reached within three months. For people who are receiving haemodialysis, intravenous iron should be the first line therapy.

What are the implications?

This review found no evidence of a difference in patient-centred outcomes between people with chronic kidney disease receiving intravenous or oral iron therapy. Doubts remain over the relative benefits for patients in terms of overall deaths, deaths caused by heart disease and quality of life.

There were greater improvements in haemoglobin levels and laboratory iron markers when using intravenous iron. Intravenous iron therapy led to more allergic reactions but fewer gastrointestinal side effects than oral therapy.

The findings are in keeping with existing NICE guidance. An approach balancing risks of adverse effects and the practicalities of delivering intravenous and oral iron therapy continues to be appropriate.

Citation and Funding

O'Lone E. L., Hodson E.M., Nistor, I et al. Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database Syst Rev. 2019;(2):CD007857.

No external funding sources were reported.

Bibliography

NICE. Chronic kidney disease: managing anaemia. NG8. London: National Institute for Health and Care Excellence; 2015.

NICE Pathways. Managing anaemia in people with chronic kidney disease. London: National Institute for Health and Care Excellence; 2017.

NHS Choices. Chronic Kidney Disease. London: NHS England; 2016.

Kidney Care UK. Anaemia. Alton: Kidney Care UK; 2019.

Kidney Care UK. Facts and Stats. Alton: Kidney Care UK; 2019.

Parenteral versus oral iron therapy for adults and children with chronic kidney disease

Published on 23 February 2019

O'Lone, E. L.,Hodson, E. M.,Nistor, I.,Bolignano, D.,Webster, A. C.,Craig, J. C.

Cochrane Database Syst Rev Volume 2 , 2019

BACKGROUND: The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. This is an update of a review first published in 2012. OBJECTIVES: To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD, including participants on dialysis, with kidney transplants and CKD not requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in which IV and oral routes of iron administration were compared in adults and children with CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We included 39 studies (3852 participants), 11 of which were added in this update. A low risk of bias was attributed to 20 (51%) studies for sequence generation, 14 (36%) studies for allocation concealment, 22 (56%) studies for attrition bias and 20 (51%) for selective outcome reporting. All studies were at a high risk of performance bias. However, all studies were considered at low risk of detection bias because the primary outcome in all studies was laboratory-based and unlikely to be influenced by lack of blinding.There is insufficient evidence to suggest that IV iron compared with oral iron makes any difference to death (all causes) (11 studies, 1952 participants: RR 1.12, 95% CI 0.64, 1.94) (absolute effect: 33 participants per 1000 with IV iron versus 31 per 1000 with oral iron), the number of participants needing to start dialysis (4 studies, 743 participants: RR 0.81, 95% CI 0.41, 1.61) or the number needing blood transfusions (5 studies, 774 participants: RR 0.86, 95% CI 0.55, 1.34) (absolute effect: 87 per 1,000 with IV iron versus 101 per 1,000 with oral iron). These analyses were assessed as having low certainty evidence. It is uncertain whether IV iron compared with oral iron reduces cardiovascular death because the certainty of this evidence was very low (3 studies, 206 participants: RR 1.71, 95% CI 0.41 to 7.18). Quality of life was reported in five studies with four reporting no difference between treatment groups and one reporting improvement in participants treated with IV iron.IV iron compared with oral iron may increase the numbers of participants, who experience allergic reactions or hypotension (15 studies, 2607 participants: RR 3.56, 95% CI 1.88 to 6.74) (absolute harm: 24 per 1000 with IV iron versus 7 per 1000) but may reduce the number of participants with all gastrointestinal adverse effects (14 studies, 1986 participants: RR 0.47, 95% CI 0.33 to 0.66) (absolute benefit: 150 per 1000 with IV iron versus 319 per 1000). These analyses were assessed as having low certainty evidence.IV iron compared with oral iron may increase the number of participants who achieve target haemoglobin (13 studies, 2206 participants: RR 1.71, 95% CI 1.43 to 2.04) (absolute benefit: 542 participants per 1,000 with IV iron versus 317 per 1000 with oral iron), increased haemoglobin (31 studies, 3373 participants: MD 0.72 g/dL, 95% CI 0.39 to 1.05); ferritin (33 studies, 3389 participants: MD 224.84 microg/L, 95% CI 165.85 to 283.83) and transferrin saturation (27 studies, 3089 participants: MD 7.69%, 95% CI 5.10 to 10.28), and may reduce the dose required of erythropoietin-stimulating agents (ESAs) (11 studies, 522 participants: SMD -0.72, 95% CI -1.12 to -0.31) while making little or no difference to glomerular filtration rate (8 studies, 1052 participants: 0.83 mL/min, 95% CI -0.79 to 2.44). All analyses were assessed as having low certainty evidence. There were moderate to high degrees of heterogeneity in these analyses but in meta-regression, definite reasons for this could not be determined. AUTHORS' CONCLUSIONS: The included studies provide low certainty evidence that IV iron compared with oral iron increases haemoglobin, ferritin and transferrin levels in CKD participants, increases the number of participants who achieve target haemoglobin and reduces ESA requirements. However, there is insufficient evidence to determine whether IV iron compared with oral iron influences death (all causes), cardiovascular death and quality of life though most studies reported only short periods of follow-up. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes with longer follow-up periods are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects.

A blood test called eGFR (estimated glomerular filtration rate) indicates roughly how well the kidneys are working to filter out waste from your blood. This function of your kidneys is categorised into five stages of chronic kidney disease.

Stages from 1 to 5 indicate a range on this blood test result:

  • Stage 1 indicates a normal eGFR (above 90ml/min), but other tests have detected signs of kidney damage
  • Stage 2 indicates a slightly reduced eGFR (60-89ml/min), with other signs of kidney damage
  • Stage 3a indicates an eGFR of 45-59ml/min
  • Stage 3b indicates an eGFR of 30-44ml/min
  • Stage 4 indicates an eGFR of 15-29ml/min
  • Stage 5 indicates an eGFR below 15ml/min, meaning the kidneys have lost almost all of their function. Patients with this kidney function will usually need the support of haemodialysis or transplant

Expert commentary

This Cochrane review provides reassurance to clinicians and patients that IV iron is effective at least in improving laboratory markers of anaemia and iron deficiency.

Questions remain about cost-effectiveness and tolerability of both oral and IV therapies. It seems reasonable to continue the widespread practice of administering IV iron when haemodialysis patients attend their dialysis unit regularly.

It remains less clear whether IV iron is cost-effective and preferable to patients who do not attend hospital so frequently, such as patients with chronic kidney disease who do not receive dialysis and patients treated with peritoneal dialysis. These groups require further study.

Mark Devonald, Consultant Nephrologist, Nottingham University Hospitals NHS Trust

The commentator declares no conflicting interests