Oral iron for people with chronic kidney disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review will look at the benefits and harms of oral iron for people with CKD.
Background
Description of the condition
Anaemia, a complication of chronic kidney disease (CKD) (Dmtrieva 2013; Fishbane 2014; Horl 2007; Macdougall 2014; McFarlane 2008), is defined as haemoglobin (Hb) levels less than 12.0 g/dL and 13.0 g/dL in adult men and women respectively (KDIGO 2012; WHO 2011). Anaemia occurs early during the course of CKD and its prevalence ranges from 25% to 70% (Hsu 2002), increasing with CKD severity (Dmtrieva 2013; Macdougall 2010; Macdougall 2014; New 2008; Stauffer 2014). Anaemia is most prevalent in people with CKD stage 5 (glomerular filtration rate (GFR) < 15 mL/min/1.73 m²) (Astor 2002; Obrador 1999).
Iron deficiency anaemia is a widespread cause of reversible anaemia (WHO 2011) frequently affecting people with CKD (KDIGO 2012; Macdougall 2014; Horl 2007). The aetiology of iron deficiency anaemia in CKD is multifactorial and includes decreased intake and absorption, increased iron demand associated with erythropoietin stimulating agent (ESA) therapy, and blood loss among people on haemodialysis (Horl 2007; Wong 2013). High levels of serum hepcidin and therapy with recombinant human erythropoietin may also result in iron deficiency (Agarwal 2004). Hepcidin, a protein produced in the liver which impairs oral iron absorption and iron liberation, is elevated among people with end‐stage kidney disease (ESKD) and uraemia because of chronic inflammation (Hodson 2014; Horl 2007).
The gold standard for diagnosis of iron deficiency anaemia is bone marrow iron stain (KDIGO 2012); however, this is an invasive test, so diagnosis is often made by iron status evaluation using transferrin saturation (TSAT) and ferritin (Fishbane 2014; KDIGO 2012). TSAT measures iron available for red blood cell production and ferritin measures iron storage (KDIGO 2012). In people with normal kidney function, ferritin levels of less than 15 µg/L in adults and 12 µg/L in children confirms diagnosis; ferritin levels greater than 100 µg/L excludes iron deficiency (Galloway 2006). Absolute iron deficiency in patients with normal kidney function has been defined by as serum ferritin levels less than 15 µg/dL in men and 10 µg/dL in women (Weiss 2005).
CKD is a chronic inflammatory condition that causes serum ferritin level elevation; and consequently, the cut‐off iron deficiency diagnosis is higher (KDOQI 2006). According to the KDIGO guidelines, serum ferritin levels ≤ 30 ng/mL is indicative of iron deficiency anaemia and predictive of low bone marrow iron stores; however, CKD patients with serum ferritin ≥ 300 ng/mL have normal bone marrow iron stores. Therefore, interpretation of ferritin in people with CKD ‐ especially haemodialysis patients ‐ should be carefully assessed because it is an acute phase reactant (KDIGO 2012; Macdougall 2010; NICE 2011).
As a result of clear evidence means that the KDIGO guidelines do not specify a definite TSAT cut‐off for diagnosis of iron deficiency anaemia in CKD. KDIGO guidelines recommend iron administration for anaemic CKD patients with TSAT < 30% and serum ferritin < 500 ng/mL (KDIGO 2012).
Description of the intervention
Inappropriate management of anaemia among people with CKD may result in decreased quality of life, increased cardiovascular disease, morbidity and mortality (Dmtrieva 2013; Horl 2007; Kassebaum 2014; Macdougall 2010; Nagaraju 2013; Wong 2013). Parenteral or oral iron therapy is recommended for CKD patients with anaemia when Hb increase (with or without ESA therapy commencement) or ESA dose decrease is required (KDIGO 2012).
Oral iron supplements are available in ferrous or ferric salts forms such as ferrous sulphate, ferrous gluconate, ferrous fumarate, ferric citrate and ferric sulphate (NIH 2014). Gastrointestinal adverse effects including nausea and constipation are common with use of ferrous or ferric salts but are seldom apparent with carbonyl iron, heme iron polypeptides, iron amino‐acid chelates and polysaccharide‐iron complexes. Adverse effects may lead to reduced therapy compliance (KDIGO 2012; Macdougall 2014; Nagaraju 2013).
The amount of elemental iron in supplements varies: ferrous gluconate, ferrous sulphate and ferrous fumarate contain 12%, 20% and 33% elemental iron respectively (NIH 2014). Ferrous sulphate 325 mg contains about 65 mg/g elemental iron and is the most common supplement. It is best absorbed on an empty stomach and may be affected by other therapies such as proton pump inhibitors, levodopa and levothyroxine (NIH 2014). Heme iron, derived from non‐vegetarian dietary intake, has a high bioavailability and accounts for more than 50% of total iron absorbed from meat‐rich diets (Hallberg 1981). Iron absorption rate is inversely proportional to its serum concentration.
This review will focus on oral iron formulations for the treatment of people with CKD‐related anaemia; intravenous iron therapy will not be addressed.
How the intervention might work
Iron is necessary for heme synthesis and red blood cell production. Normal iron content in the body is 3 g to 4 g (Camaschella 2011). Iron homeostasis is regulated by intestinal absorption and release of iron from macrophages (Camaschella 2011).
Oral iron is recommended as initial therapy for people with CKD‐related anaemia who are not receiving dialysis, other forms of iron supplementation, or ESA therapy. Concomitant iron deficiency anaemia during ESA therapy may decrease treatment response (Horl 2007; Nagaraju 2013; Wong 2013).
Why it is important to do this review
Intestinal iron absorption may be limited among people with ESKD (Kooistra 1998) and parenteral iron may be more effective for CKD (Agarwal 2006; Van Wyck 2005), haemodialysis (Markowitz 1997) and peritoneal dialysis patients (Johnson 2001; Vychytil 1999). Tsuchida 2010 has reported that with the use of ultra‐pure dialysate, oral iron is as effective as IV iron in managing anaemia for haemodialysis patients because it maintains iron indices and is well tolerated. However, there is lack of consensus about the efficacy of oral iron supplements. A Cochrane review (Albaramki 2012) showed significant increase in Hb, ferritin and transferrin saturation among patients receiving parenteral iron compared with those on oral iron. Albaramki 2012 found that although gastrointestinal side effects were higher with oral iron and hypotension and allergic reactions more common with parenteral iron, mortality and cardiovascular morbidity were similar.
Oral iron has several advantages including ease of administration (KDIGO 2012; Macdougall 2014), low cost (KDIGO 2012; Macdougall 2014; Nagaraju 2013), availability, and no requirement for intravenous access. This review will examine the overall effectiveness and reported adverse effects of oral iron preparations. Albaramki 2012 assessed the efficacy of intravenous versus oral iron supplements. Our review will evaluate oral iron supplements compared with placebo, no treatment or other oral iron supplements.
Objectives
This review will look at the benefits and harms of oral iron for people with CKD.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the benefits and harms of oral iron for people with CKD.
Types of participants
Inclusion criteria
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People of any age or gender with all stages of CKD who were undergoing conservative management or dialysis.
Exclusion criteria
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Studies including comparisons involving intravenous iron preparations (which have been addressed in Albaramki 2012)
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People who have undergone kidney transplantation.
Types of interventions
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Comparison of different oral iron preparations
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Oral iron versus placebo or no specific treatment
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Different doses of oral iron
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Oral iron alone versus oral iron plus another medication (e.g. vitamin C or ESA).
Participants receiving interventions 1, 2 or 3 may also have received ESA therapy.
Types of outcome measures
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Mean Hb at study end
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Change in Hb at study end
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Gastrointestinal adverse events (measured as the rate of reported gastrointestinal adverse events in treatment versus control arms)
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Proportion of patients achieving target Hb
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Kidney function measures (e.g. creatinine clearance, serum creatinine (SCr), proteinuria, dialysis, GFR) as reported in studies
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End of treatment or change in serum ferritin levels
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End of treatment or change in % transferrin saturation levels
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Change in ESA dose
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Cardiovascular morbidity
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Other adverse events as reported by the authors of primary studies
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Quality of life measures as reported by authors of primary studies
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Cardiovascular mortality
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All‐cause mortality.
Primary outcomes
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Mean Hb or change in Hb at study end (measured as the mean difference in Hb between treatment arms or change in Hb respectively)
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Gastrointestinal adverse events (measured as the rate of reported gastrointestinal adverse events in the treatment versus control arms).
Secondary outcomes
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Withdrawal from treatment measured as withdrawal rates from the intervention versus control arms
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All‐cause mortality to be measured as the mortality rates in the intervention versus control arms
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Cardiovascular mortality
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Cardiovascular morbidity for example non‐fatal myocardial events, hospitalisation for cardiovascular events, and stroke
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Kidney function measures (e.g. GFR, SCr) as reported by authors of primary studies
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End of treatment or change in serum ferritin levels
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End of treatment or change in % transferrin saturation levels
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Change in ESA dose
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Quality of life measures as reported by authors of primary studies
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Adverse events other than gastrointestinal.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials Search Co‐ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials CENTRAL
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Weekly searches of MEDLINE OVID SP
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Handsearching of kidney‐related journals and the proceedings of major kidney conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected kidney journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
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Reference lists of review articles, relevant studies and clinical practice guidelines.
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Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. Titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however, studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts, and if necessary, the full text of studies to determine which satisfy the inclusion criteria.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions this data will be used. Any discrepancy between published versions will be highlighted.
Assessment of risk of bias in included studies
The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).
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Was there adequate sequence generation (selection bias)?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
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Participants and personnel
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Outcome assessors
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (e.g. withdrawal from treatment, death) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (Increase in Hb, mean Hb at the end of treatment, eGFR), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales had been used.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence (e.g. emailing corresponding author/s) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol population will be carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) will be critically appraised (Higgins 2011).
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).
Data synthesis
Data will be pooled using the random‐effects model but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. adults versus children; pre‐dialysis versus dialysis patients; haemodialysis versus peritoneal dialysis groups; various iron preparation types; patients on ESAs and oral iron versus oral iron alone; study quality). Heterogeneity among participants could be related to age and renal pathology (e.g. sickle cell nephropathy patients may be resistant to ESAs and iron therapy). Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy (e.g. patients previously on oral iron or repeated blood transfusions). Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
Sensitivity analysis
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size.
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Repeating the analysis excluding unpublished studies
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Repeating the analysis taking account of risk of bias
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Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
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Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
