Oral nutritional supplement helps to improve nutritional status of dialysis dependent patients: a systematic review and meta-analysis of randomized controlled trials

Background The prevention and treatment of malnutrition holds remarkable implications in the overall management of dialysis patients. However, there remains a dearth of comprehensive evaluations regarding the impact of oral nutrition supplement (ONS) on all pertinent dimensions of malnutrition in the dialysis population. Methods A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Library. RCTs that had assessed the effects of oral nutritional supplement in dialysis-dependent populations were considered eligible. Outcomes included laboratory indicators, anthropometric measures, nutritional indices, dialysis adequacy, body composition analysis measures, and systemic inflammation indicators. The risk of bias was assessed according to Cochrane guidelines. Weighted mean difference (WMD) or standardized mean difference (SMD) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results In all, 22 RCTs with 1,281 patients were included. The pooled analyses revealed the serum ALB, BMI, nPCR, and MIS improved by 1.44 g/L (95% CI: 0.76, 2.57), 0.35 kg/m2 (95% CI: 0.17, 0.52), 0.07 g/(kg d) (95% CI, 0.05, 0.10), and −2.75 (95% CI, −3.95, −1.54), respectively following ONS treatments when compared to control treatments. However, no significant differences were observed in relation to the other outcomes examined. 15 studies were rated as having high risk of bias. Visual inspection of the funnel plot and Egger test argued against the presence of publication bias. Conclusion ONS treatments helps to improve the nutritional status of dialysis dependent patients. More evidence is needed from future investigations with longer study duration and standardized procedures to support long-term use of ONS in this population. Systematic review registration https://www.crd.york.ac.uk/prospero/, Identifier CRD 42023441987.


Introduction
Malnutrition is highly prevalent among dialysis dependent patients (1,2).The nutrients deficiency arises from a confluence of factors, namely reduced absorption of nutrients due to symptoms associated with renal failure, such as gastrointestinal discomfort, diminished appetite, acidosis, and depression, as well as the loss of nutrients during dialysis sessions, including proteins, glucose, and amino acids (3).Furthermore, malnutrition in renal failure patients can also be attributed to protein energy wasting (PEW), which is characterized by aberrant protein metabolism, progressive loss of skeletal muscle mass, low levels of serum albumin, and microinflammatory status (4).
Malnutrition significantly exacerbates the unfavorable prognosis of dialysis patients by interacting with the microinflammatory status, leading to accelerated development arterial disease which are closely associated with cardiovascular mortality (5).The compromised nutritional status of these patients places them at a heightened susceptibility to infectious disease and the subsequent catastrophic outcomes following severe infections.In addition, malnutrition complicates the correction of mineral and bone metabolism disorders.Therefore, the prevention and treatment of malnutrition holds remarkable implications in the overall management of dialysis patients (2).
Nutrition interventions have been demonstrated to be effective in improving the condition of dialysis patients (6).Among the various interventions, oral nutrition supplement (ONS) is considered an important strategy (6,7).The commercially available ONS agents are not only convenient to consume, but have also been shown to effectively address malnutrition in dialysis patient without causing electrolytes disturbances, including calcium, phosphorus, and potassium (8).However, there remains a dearth of comprehensive evaluations regarding the impact of ONS on all pertinent dimensions of malnutrition in the dialysis population.
Therefore, we conducted this systematic review and meta-analysis to comprehensively synthesize the existing evidence on the use of ONS in dialysis dependent patients.The primary objective was to exam a wide range of outcomes pertaining to malnutrition in dialysis population, while prioritizing randomized clinical trials to ensure the highest level of evidence.

Data sources and searches
A systematic search was conducted for eligible studies published up to July 17th, 2023 in EMBASE via Ovid, MEDLINE via PubMed, and Cochrane Central Library via Ovid according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement (9).The search terms used text words relevant to chronic kidney disease, randomized clinical trial, and oral nutritional supplement (Supplementary Table S1).The study had been registered on PROSPERO (Identifier# CRD 42023441987).

Study selection
Randomized clinical trials (RCTs) that had assessed the effects of oral nutritional supplement in dialysis-dependent populations were considered eligible for this study.There was no restriction on the nutritional agents in the supplement treatment or dialysis strategies.
The screening was conducted by two reviewers (SR and XY) independently following a standardized approach.The titles and abstracts of all returned records from database searching were carefully reviewed.Duplicates, non-original studies (e.g., reviews, editorials, commentaries, guidelines, proceedings, and secondary or subgroup analyses of RCTs), study protocols, case reports, animal studies, studies irrelevant to nutritional supplement, and studies in non-dialysis populations were excluded.Reference lists from the resulting articles after full text review were manually scanned to identify any relevant studies.Any discrepancy was resolved by a third reviewer (YF).

Outcomes
This systematic review considered different aspects that could reflect the effects of nutritional supplement in dialysis-dependent patients.Briefly, these outcomes reflecting nutrition status were classified into the following six types: (1)

Data extraction and quality assessment
Data from eligible studies were extracted by two reviewers (SR and XY) independently and compiled after cross-check.Any discrepancy was resolved by the third reviewer (YF).The extracted data included names of the first author, year of publication, geographical origin, number of patients in the overall study population, numbers of patients in the ONS and control groups, details of the ONS interventions, details of the control treatments, and details of reported outcomes.Information about potential sources of heterogeneity, such as the study intervals and sex makeup of the study population, was also collected for subgroup analysis.

Critical appraisal of included studies
The risk of bias was independently assessed by two reviewers (SR and YF) based on the "Cochrane Handbook for Systematic Reviews of Interventions" imbedded in analysis software (10).

Data synthesis and analysis
Data analysis and synthesis were conducted using Stata, version 17.0 (Stata) and RevMan, version 5.2 (RevMan).All studied outcomes were continuous variables.Means and standard deviations of changes from baseline were extracted (if reported in the original study) or calculated by subtracting the baseline values from the values after treatments based on a published equation (8).Weighted mean difference (WMD) or standardized mean difference (SMD) with 95% confidence intervals (CIs) Frontiers in Nutrition 03 frontiersin.org were pooled using a random-effects model.Statistical heterogeneity was estimated using the I 2 statistic (11).In studies that reported more than one invention of ONS, each intervention was treated as one independent interventional group and compared with the control treatment.The pooled results of individual outcomes were deemed having low, moderate, and high statistical heterogeneity if I 2 was <25%, between 26% and 75%, and >75%, respectively (11).Subgroup analyses were also conducted based on the follow-up duration and dialysis mode.Publication bias was assessed using funnel plot analysis and Egger test.p-value of <0.05 was considered statistically significant.

Search findings
One hundred thirty-six records were returned from the literature searching.After removing 21 duplicates and 86 articles by screening the titles and abstracts, 29 publications were left for full text review, among which 7 studies were further excluded.Finally, 22 studies encompassing 1,281 patients were included in this systematic review and meta-analysis (12-33) (Figure 1).

Effects of ONS on laboratory indicators
The pooled analysis indicated that ONS treatments significantly improved the serum ALB by 1.44 g/L (95% CI: 0.76, 2.57, p < 0.001) yet with high heterogeneity (I 2 = 68.0%,p < 0.001) (Figure 2); however, the ONS treatments did not show significant effects on the levels on other laboratory indicators, including pre-ALB, hemoglobulin, electrolytes (Supplementary Figure S1), or lipid (Supplementary Figure S2).

Effects of ONS on anthropometric and body composition analysis measures
The pooled analysis indicated the ONS treatments significantly improved the BMI by 0.35 kg/m 2 (95% CI: 0.17, 0.52, p = 0.002) with moderate heterogeneity (I 2 = 43%, p = 0.03) (Figure 3).The changes of MAC and MAMC values after the ONS treatments did not differ from those after the control treatments.The pooled analysis indicated the ONS treatments did not change the fat mass or the lean mass derived from body composition analysis (Figure 4).

Effects of ONS on dialysis adequacy and inflammation indicators
The dialysis adequacy reflected by Kt/V did not show significant improvement after the ONS treatments compared to the control treatments, nor the levels of CRP and IL-6 (Figure 6).

Subgroup analyses
To further explore the heterogeneities of four outcomes that exhibited significant improvement after ONS treatment, namely ALB, BMI, nPCR, and MIS, subgroup analyses based on follow up duration and dialysis mode were conducted.The results indicated the improvement of the nPCR insignificantly increased with longer study duration, whereas the improvement of ALB, BMI, and MIS after ONS treatments was only significant in patients receiving treatments less than 3 months (Supplementary Figure S3).Similarly, the improvement of ALB, BMI, and MIS after ONS treatments was only significant in HD populations, whereas the improvement of the nPCR was significant both in HD and PD populations (Supplementary Figure S4).

Critical appraisal
Based on the Cochrane criteria, none of the included studies had low risk of bias (Supplementary Figure S5).Fifteen studies were rated as having high risk of bias.The mostly common reason for high risk of bias was the lack of double blindness in the study design in all except for three studies.

Publication bias
Visual inspection of the funnel plot revealed relative symmetry, arguing against the presence of publication bias (Supplementary Figure S6).This finding was supported by the results of Egger test (p = 0.973).There were 5 studies outside the plot, indicating the presence of heterogeneity.

Discussion
The results of this systematic review and meta-analysis suggest that ONS treatment helps to improve the nutritional status of dialysis dependent patients by exhibiting a positive impact on BMI, serum ALB, nPCR, and MIS when compared to control treatments.However, no significant differences were observed in relation to the other outcomes examined.It is important to note that a majority of the studies included in our analysis were deemed to have a high risk of bias.
Oral supplementation of energy, protein, or lipid has been shown to be advantageous for patients dependent on dialysis (8).To comprehensively cover currently available nutritional treatment options, this study considered various forms of supplements, from commercially available lipid fluid to selfformulated supplements, from a mixture of multiple nutrients to a single nutrient such as vitamin E. Taken together, our findings revealed that ONS treatments resulted in significant improvements in BMI, serum ALB, and nPCR levels, without affecting electrolyte levels that are susceptible to dietary influences such as phosphorus, which align with existing literature (8).It should be noted the wide variations in the types of ONS included in this meta-analysis might be a source of the observed heterogeneities.Other potential sources of the heterogeneities include the nutritional status in the inclusion criteria, dialysis vintage of the population, duration of treatment, and dialysis mode.The results of subgroup analyses indicated the improvement of ALB, BMI, and MIS after ONS treatments was significant in HD populations and in patients receiving shortterm treatment, and the improvement in nPCR was not affected by dialysis mode or treatment duration, suggesting the benefits of ONS might be more easily observed in HD patients.
This study is the first to report evidence of improved MIS following ONS treatments through a meta-analysis of results from RCTs.The MIS serves as a comprehensive evaluation of nutritional status of dialysis patients from four dimensions (4,5).The MIS reflects the risk of malnutrition and has been reported to significantly correlate with morbidity and mortality in maintenance dialysis patients (3,34,35); therefore, the improvement in the MIS is of important clinical relevance in this population.The frontiersin.orgThe absence of discernible advantages of ONS treatments compared to control treatments across all various outcomes investigated may be attributed to the multifaceted nature of nutritional status, which is influenced by factors far beyond oral intake alone.Even oral intake itself is significantly influenced by various factors, The potential influence of study duration on the impact of ONS on nutritional indices should also be taken into account.The outcomes on which ONS exhibited beneficial effects in this study, namely BMI, serum ALB, nPCR, and MIS, were all short-term outcomes.These measures provide rapid indications of changes in nutritional status within the body.Conversely, longer treatment durations may be necessary to observe any changes in long-term outcomes, such as MAC and MAMC derived from anthropometry.In addition, the adherence to ONS is an important component in the long-term management of renal failure patients, which might be enhanced by early onset of beneficial effects and professional patient education.Another important consideration of ONS is the cost, particularly in regions where commercially available ONS agents are relatively expensive and not covered by social medical insurance.Long-term use of ONS needs supportive evidence from cost-effective analysis.
The current study benefited from its comprehensive evaluation encompassing multiple facets of malnutrition in dialysis patients, including laboratory indicators, anthropometric measures, dialysis adequacy, diet evaluation, body composition analysis measures, and systemic inflammation indicators.There are several limitations that should be acknowledged.Firstly, a majority of the studies included in the analysis (13 out of 21) had a sample size of less than 50.Secondly, 14 out of the 21 studies were determined to have a high risk of bias, which hinders the ability to draw strong and reliable conclusions.Thirdly, the control treatments utilized in the included studies varied significantly, potentially introducing interference in the comparison.Lastly, due to a lack of reporting, we were unable to assess the impact of ONS on longterm outcomes, as the longest study duration was limited to 6 months.

Conclusion
This systematic review and meta-analysis suggest that ONS treatments help to improve nutritional status among dialysis dependent patients by exhibiting a positive impact on BMI, serum ALB, nPCR, and MIS when compared to control treatments.More evidence is needed from future investigations with longer study duration and standardized procedures to support long-term use of ONS in this population.

FIGURE 3
FIGURE 3 Pooled analysis of the effects of ONS treatment on anthropometric measures: (A) BMI; (B) MAC; (C) MAMC.Abbreviations: BMI, body mass index; MAC, mid arm circumference; MAMC, mid arm muscle circumference.

FIGURE 4
FIGURE 4Pooled analysis of the effects of ONS treatment on body composition analysis measures: (A) Fat mass; (B) Lean mass.