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Cochrane Database of Systematic Reviews Protocol - Intervention

Oral protein‐based supplements for people with chronic kidney disease requiring dialysis

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

This review aims to look at the benefits and harms of using oral protein‐based supplements to improve the nutritional state of patients with CKD requiring dialysis.

Background

Description of the condition

The number of people estimated to be receiving renal replacement therapy worldwide increased from 1.1 million during the 1990 to 2.618 million in 2010 (Liyanage 2015; Lysaght 2002). Malnutrition is common in patients with chronic kidney disease (CKD) on dialysis. A prospective cohort study by Tan 2016 found that more than half of hospitalised patients requiring haemodialysis (HD) were malnourished. In fact, malnutrition can already be demonstrated in about 10% of renal patients at the start of predialysis care (Westland 2015).

Several factors are thought to contribute to malnutrition in dialysis‐dependent patients. These include, but are not limited to, reduced oral intake and loss of appetite due to uraemic toxins, increased catabolism, low‐grade inflammation, oxidative stress, and the presence of other co‐morbidities (Burrowes 2003; Malgorzewicz 2016). An additional issue for hospitalised patients includes frequent fasting for tests and procedures.

Malnutrition is defined as a low‐nutrient intake or an intake that is inadequate for the nutritional needs of the individual (Fouque 2008a). Nutrition assessment tools frequently used in assessing malnutrition among dialysis patients include the Subjective Global Assessment (SGA) and the patient‐generated SGA (PG‐SGA) (Desbrow 2005; Detsky 1987). In dialysis patients, malnutrition has been strongly associated with increased mortality and hospitalisations, as well as poor quality of life (Dwyer 2002; Kalantar‐Zadeh 2001; Kalantar‐Zadeh 2011). Of the several clinical factors evaluated in the dialysis population, advanced age has been associated with a higher incidence of malnutrition (Kadiri 2011).

Description of the intervention

Dietary energy and protein intake of patients on maintenance HD are inadequate compared to the recommended standard of care, which can result in loss of lean body mass and malnutrition (Burrowes 2003; KDIGO 2012). The Kidney Disease Improving Global Outcomes (KDIGO) Guidelines recommend that individuals with CKD receive expert dietary advice and information in the context of an educational program that is tailored to the severity of the disease (KDIGO 2012).

Oral nutritional (protein and calorie) supplements are often provided to patients whose oral intake is otherwise insufficient to meet their energy needs (Jensen 2013). They are typically formulated as a combination of macro and micronutrients, and are used in conjunction with expert advice from dietitians (Jensen 2013; Schneyder 2014). Standard oral nutritional supplements are best taken as snacks between meals to complement normal meals (Schneyder 2014).

How the intervention might work

Diet and enteral nutritional support that targets dietary protein intake have previously been reported to mitigate malnutrition (Kalantar‐Zadeh 2011). However, appropriate nutritional supplements can be difficult to administer in dialysis patients. In addition to factors such as a reduced appetite, poor nutrition is further compounded by the dictates of a stringent fluid restriction, especially in patients with minimal urine output, and electrolyte imbalance. High protein foods such as meat, dairy and nuts carry a high phosphate load, and 'healthy' foods such as fruit and vegetables are often restricted because of their potassium content. Oral nutritional supplements therefore must be suitably adjusted in order to be taken safely and repeatedly. As such, renal‐specific supplements have a higher protein and energy content, with a lower potassium and phosphate content (Williams 2009). Examples of protein‐based oral nutritional supplements prescribed to dialysis patients include Nepro, Novasource Renal, Renilon, and Suplena (Fouque 2008b; Shah 2014). Protein isolates which include, but are not limited to, whey protein and soy protein, have also been used as a source of protein supplementation in dialysis patients (Tomayko 2015).

Reported benefits of oral nutritional supplements in HD patients include improvement in muscle quality leading to improvements in physical function without an increase in lean mass (Franch 2009; Tomayko 2015). The use of oral nutritional supplements may also provide quicker nutritional repletion and a trend towards a reduced number of days of hospitalisation (Wilson 2001). Reported harms include adverse biochemistry (hyperkalaemia, hyperphosphataemia), intolerability due to taste, and cost that is often borne by the patient (Williams 2009).

Why it is important to do this review

The benefits of protein‐based oral supplements in patients with CKD, particularly those on dialysis, have long been debated. However, several recent, large, observational studies have demonstrated that the use of oral intra‐dialytic nutritional supplements is associated with a reduction in mortality of up to 35% in HD patients (Lacson 2012; Weiner 2014).

The cost of oral nutritional supplements is usually borne by the patients. The increasing expenditure of such supplements further complicates the picture. A recent systematic review by Elia 2016, based mostly on retrospective cost analyses, indicated that the use of nutritional supplements in the community and care homes produce an overall cost advantage. This cost advantage was primarily from reduced hospitalisations and length of stays, but there were also several clinically relevant outcomes favouring oral nutritional supplements reported, including an improved quality of life and reduced infections (Elia 2016). Focusing on the subgroup analyses comparing the use of oral nutritional supplements to no oral nutritional supplements, there is a median cost saving of 11.5% (Elia 2016).

Baldwin 2011 conducted a systematic review examining several interventions in addition to dietary advice in adults with disease‐related malnutrition. One intervention arm of this review compared the outcome of dietary advice with dietary advice plus an oral nutritional supplement (Baldwin 2011). Improvements in mid‐arm muscle circumference, triceps skinfold, and grip strength were demonstrated in the supplement group (Baldwin 2011). However, for the two latter outcomes, there was significant heterogeneity in the pooled analysis (Baldwin 2011). In this intervention arm though, only three of the 16 studies included involved patients on dialysis (Baldwin 2011). Furthermore, as this review was completed in 2011 and the terms 'dialysis or CKD' were not specifically used in their search terms, there may be studies specific to dialysis patients available now that were not included in their analysis (Baldwin 2011).

The focus of this review is the role of oral protein‐based supplements in patients with CKD on dialysis. Although the above reviews by Elia 2016 and Baldwin 2011 are not specific to dialysis patients, it certainly raises the question whether potential benefits in clinical outcomes and cost are applicable to the dialysis population more generally. Currently, there are no consensus guidelines regarding the use of oral nutritional supplements in dialysis patients. As such, the availability and prescription of oral protein‐based supplements varies widely between dialysis units. Understanding the relevant benefits, cost restrictions and potential for harm with their use will likely lead to a more consistent approach.

Objectives

This review aims to look at the benefits and harms of using oral protein‐based supplements to improve the nutritional state of patients with CKD requiring dialysis.

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) comparing oral protein‐based supplements to no oral nutritional supplements will be included without language restriction.

If the search strategy reveals a large number of trial comparing different types of oral protein‐based supplements, consideration will be given to examine the outcomes with these comparisons in separate analyses.

Types of participants

We will include adults with CKD on dialysis, which encompasses both HD and peritoneal dialysis (PD).

Studies of patients with kidney disease not requiring dialysis, including conservative care and kidney transplant recipients, will be excluded.

Types of interventions

Studies comparing oral protein‐based supplements to no oral protein‐based supplements or placebo will be included. These supplements include renal‐specific supplements such as Nepro, Novasource Renal, Renilon, and Suplena, as well as protein isolates including whey and soy protein. Studies where dietary advice is provided to the non‐intervention group will be included.

Types of outcome measures

Assessment of nutritional status in patients receiving dialysis takes into account multiple factors and no single measure of nutritional status is sufficient on its own. We have therefore included both physical and biochemical measures of nutritional status as outcomes and will report on these as the data allows.

Primary outcomes

  1. Changes in serum albumin level

  2. Other measure of nutritional status (such as weight gain, serum prealbumin level, anthropometric measurements, e.g. triceps skin fold thickness and arm muscle circumference, grip strength)

  3. Mortality

  4. Intolerance to therapy

Secondary outcomes

  1. Quality of life

  2. Cost

  3. Markers of inflammation

  4. Biochemical adverse effects such as hyperkalaemia or hyperphosphataemia

Search methods for identification of studies

Electronic searches

We will search the Cochrane Kidney and Transplant Specialised Register through contact with the Information Specialist using search terms relevant to this review. The Cochrane Kidney and Transplant's Specialised Register contains studies identified from several sources.

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of kidney‐related journals and the proceedings of major kidney conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected kidney and transplant journals

  6. 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 Cochrane Kidney and Transplant. 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 Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of review articles, relevant studies and clinical practice guidelines

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies

  3. Clinical trial registries for studies not yet completed.

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. The 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 these studies to determine which studies satisfy the inclusion criteria. Any differences will be resolved by discussion and where necessary, by consultation with a third author.

Data extraction and management

Two authors will independently extract data using ‘data extraction forms’ which will be developed. 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 these 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).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study?

    • Participants and personnel (performance bias)

    • Outcome assessors (detection bias)

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • 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. mortality, episodes of hyperkalaemia) 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 (e.g. change in serum albumin levels, anthropometric measures and weight), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.

Unit of analysis issues

Studies with non‐standard designs will be analysed in this review using the recommended methods for data extraction and analysis described by The Cochrane Collaboration (Higgins 2011).

When considering cross‐over studies, we will only include data for end points reported during the first period of study in studies in which the order of receiving treatments was randomised.

When considering studies with multiple treatment groups, we will attempt to combine all relevant experimental intervention groups of the study into a single group and to combine all relevant control intervention groups into a single control group to enable a single pair‐wise comparison.

Cluster‐randomised trials will be analysed using a statistical analysis that properly accounts for the cluster design as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing and/or writing to 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 will be critically appraised (Higgins 2011).

Assessment of heterogeneity

We will first assess the heterogeneity by visual inspection of the forest plot. Heterogeneity will then 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). A guide to the interpretation of I2 values will be as follows.

  • 0% to 40%: might not be important

  • 30% to 60%: may represent moderate heterogeneity

  • 50% to 90%: may represent substantial heterogeneity

  • 75% to 100%: considerable heterogeneity.

The importance of the observed value of I2 depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi2 test, or a confidence interval for I2) (Higgins 2011).

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. participants, interventions and study quality). Heterogeneity among participants could be related to age, co‐morbidities, severity of malnutrition (low versus high baseline albumin level), and PD versus HD. Furthermore, patients with reduced food intake may be more likely to benefit from the intervention than those whose intake is considered adequate. Therefore, subgroup analysis of studies that include patients with reduced versus adequate intake will be performed. Heterogeneity in treatments could be related to dose, type and duration of protein‐based oral supplements. Adverse effects will be tabulated and assessed with descriptive techniques. Where possible, the risk difference with 95% CI will be calculated for each adverse effect in the treatment group compared to placebo.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size.

  • Repeating the analysis excluding unpublished studies

  • Repeating the analysis taking account of risk of bias, as specified

  • Repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.

'Summary of findings' tables

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We plan to present the following outcomes in the 'Summary of findings' tables.

  • Changes in serum albumin level

  • Other measures of nutritional status (such as weight gain, serum prealbumin level, anthropometric measurements, e.g. triceps skin fold thickness and arm muscle circumference, grip strength)

  • Mortality

  • Intolerance to therapy

  • Quality of life

  • Cost

  • Markers of inflammation

  • Biochemical adverse effects such as hyperkalaemia or hyperphosphataemia.

These outcomes will be presented in two tables.