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.

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.

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.