1. Introduction
Chronic kidney disease (CKD) is a common chronic condition with an estimated global prevalence of approximately 10% [
1]. In recent years, the medical strategy for CKD has included recommendations for cures for comorbidities, the prevention of complications during treatment, the avoidance of nephrotoxic drugs, and proper dietary management [
2,
3]. Dietary modification was previously shown to reduce the accumulation of uremic toxins and excess minerals, such as potassium and phosphates. These benefits not only improve symptomatic relief but also slow the loss of renal function, thus delaying the onset of dialysis [
4].
One of the foundations of this therapeutic approach is the restriction of protein intake to levels of approximately 0.55–0.6 g/kg/day in nondiabetic CKD patients and 0.6–0.8 g/kg/day in diabetic CKD patients [
5,
6]. The success of implementing nutritional interventions in CKD patients is dependent upon the patient’s adherence to a low-protein diet (LPD). Protein restriction changes the eating habits of CKD patients and must, therefore, be intensively followed by a renal dietitian [
7]. LPD implementation is both patient-centered and personalized to help with compliance, efficacy, and safety, and it involves referral from a nephrologist to a dietitian as medically prescribed care [
8]. Furthermore, using a simplified and easy-to-follow dietary regimen may improve one’s adherence to an LPD [
9]. The energy requirements in CKD are recommended to be 25–35 kcal/kg/day [
5]. Poor appetite induced by uremia and protein restriction may lead to insufficient caloric intake, with these factors possibly causing protein–energy wasting (PEW) [
10]. In addition to LPD control, individual diet prescriptions can be implemented in pre-dialysis CKD patients for one or more of sodium, phosphorus, and potassium, as determined by electrolyte or renal function [
11]. There is no adequate energy supply in the prescription of a CKD diet; hence, oral nutritional supplements (ONSs) are considered a next step [
12].
Previous research has shown that low-protein ONSs can improve both adherence to an LPD and nutritional status during pre-dialysis CKD [
13,
14,
15,
16]. Currently, the use of ONSs as complete or partial meal replacements has been studied, including diabetes-specific ONSs for improving glycemic control in diabetes patients [
17] and high-protein ONSs for weight control in obese patients [
18,
19]. However, few studies have investigated low-protein ONSs in pre-dialysis CKD patients. The aim of this study was to evaluate the efficacy and safety of a high-energy, low-protein formula (HE-LPF) that was tailored to suit the nutritional management approach for pre-dialysis CKD patients as either a complete or a partial meal replacement in terms of changes in anthropometric measurements, dietary intake, clinical parameters, adherence, and adverse events.
2. Materials and Methods
2.1. Study Design
This study was a single-center, prospective, randomized, open-label, controlled, parallel-group trial that was carried out with pre-dialysis stage 4–5 CKD patients during a 4-week study period. Patients were recruited over a period of 8 months from the end-stage renal disease program database within the renal clinical service department of Taichung Veterans General Hospital during the period from April to December 2020. Eligible participants were assigned at a 1:1 ratio to either the HE-LPF group or the control group using computer-generated randomization to receive either the study intervention or a control comparator. The study was carried out according to the current version of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines, with reference to a study protocol approved by the Institutional Review Board of Taichung Veterans General Hospital (IRB approved number SF20045B). Signed and dated informed consent was obtained from all patients prior to enrollment in the study. The trial was registered at ClinicalTrials.gov (NCT05330663).
2.2. Subjects
Subjects meeting the following inclusion criteria were eligible for study: aged between 20 and 80 years, having an eGFR of <30 mL/min/1.73 m2 at screening, and having followed a low-protein diet that provided a protein level of 0.6–0.8 g/kg/day for at least 3 months prior to inclusion. The exclusion criteria were incident or prevalent dialysis, potential for renal transplantation, a body mass index (BMI) of <18 or >30 kg/m2, pregnancy or lactation, malnutrition with albumin levels of <3 g/dL with the need for caloric and other nutritional supplements, severe liver disease, malignancy or infectious disease, existing gastrointestinal disease or pathological findings contraindicating enteral nutrition (including intestinal ileus, acute upper gastrointestinal bleeding, malabsorption or maldigestion conditions, or previous significant surgical resection of the intestine, as well as dysphagia or high risk of aspiration), severely impaired gastrointestinal function (including severe constipation or acute diarrhea), relevant central nervous system and/or psychiatric disorders, known allergies or intolerance to any ingredient in the study product, planned surgery or hospitalization during the study period, suspicion of drug abuse, participation in another clinical trial within 30 days of the study’s start and for the duration of the study, and the inability to comply with the study’s instructions and procedures.
2.3. Dietary Management
A registered dietitian calculated the individual nutritional requirements for each patient in order for them to obtain the required 0.6–0.8 g/kg/day of protein and 25–35 kcal/kg/day of energy using their actual body weight according to clinical practice guidelines for the dietary management of CKD [
5]. Keto-analogues were used where clinically appropriate on an individual patient basis to ensure an adequate supply of nitrogen-free precursors of essential amino acids. Before participating in the study, subjects were asked to maintain their usual CKD management behaviors and lifestyle (e.g., medications and exercise). Subjects received diet counseling from the same registered dietitian at the beginning of the study and again at 2 weeks to maximize the achievement of their nutritional goals.
2.4. Study Intervention
The intervention group was given a replacement for a single, typically high-protein meal or part of a meal (preferably breakfast) according to their dietary habits during the day. The HE-LPF consisted of 200 mL units (Fresubin
® Renal Drink providing 400 kcal, 6% of energy from protein, and reduced electrolytes, and containing fish oil and dietary fiber) with the composition shown in
Supplementary Table S1. The control group received normal food (conventional care) during the 4-week study period. All patients returned to follow-up at week 2 and week 4 with 3-day food records. The dietitian then recommended a diet prescription according to the dietary habits of each patient. All patients in both groups continued to follow an LPD.
2.5. Efficacy Assessments
The efficacy endpoint was analyzed according to anthropometric indicators and dietary intake. The primary endpoint of efficacy was a change in body weight. Anthropometric measurements of body composition, grip strength, and waist circumference were all used to assess nutritional status. Body composition was determined using the Tanita MC-780 (TANITA Corporation, Akita, Japan) bioelectric impedance analysis technology, which involved measurement of body weight (BW, kg), body mass index (BMI, kg/m2), percentage body fat (%), fat mass (kg), muscle mass (kg), extracellular water (kg), and fat-free mass (kg). Grip strength was measured using a TTM-YD model hand dynamometer (Tsutsumi industries, Tokyo, Japan). Waist circumference was measured at the level of the iliac crest while the subject breathed minimally. The intake of energy, protein, carbohydrates (CHOs), saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)), and the main minerals (sodium, potassium, calcium, phosphorus, and magnesium) was evaluated using 3-day food records. Energy and nutrients were calculated using the e-Kitchen system (2017 version, with the Taiwan Food and Drug Administration reference tables for food composition).
2.6. Safety and Adherence Assessments
The safety endpoint was analyzed using biochemical parameters, adherence, and adverse events. Biochemical parameters were collected using blood, including blood nitrogen urea (BUN), creatinine (Cr), sodium, chloride, potassium, calcium, phosphorus, magnesium, albumin, prealbumin, total protein, C-reactive protein (CRP), cholesterol, triglycerides, uric acid, low-density lipoprotein (LDL), and glycated hemoglobin (HbA1C). The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [
20]. A 24 h urine sample was collected to measure urine protein and urine urea nitrogen (UUN), and the Maroni equation was used to calculate dietary protein intake [
21]. Adverse events were evaluated according to gastrointestinal symptoms (including diarrhea, abdominal distention, constipation, nausea, and vomiting). Adherence to the prescribed interventional product was evaluated at weeks 2 (the first two weeks) and 4 (the final two weeks). To calculate adherence, patients in the intervention group kept a diary of their actual consumption of the food eaten within their low-protein diet. According to an evaluation by their dietitian and the nutritional content of the chosen meal, an interventional drink was included as either a complete or partial meal replacement.
2.7. Statistical Analysis
The calculated sample size involved 78 subjects based on a power of 80% using ANOVA: repeated measures between factors, two groups, three time points, and an effect size of 0.25 at the α = 0.05 significance level. The sample size was estimated using G * Power version 3.1.9.7 (a program written by Franz Faul, Universität Kiel, Germany) [
22]. Assuming an approximately 5% dropout rate, we estimate that 84 patients were enrolled in the study. Data are presented as means (standard deviation; SD) and counts (percentages; %). The intention-to-treat (ITT) population was defined as subjects who completed all visits. The per-protocol (PP) population was defined as patients in the HE-LPF group who planned to use one bottle a day of an HE-LPF ONS to replace a high-protein meal or part of a meal, with adherence exceeding 85%. Analysis of the efficacy and safety outcomes in the ITT and PP populations was performed. Exploratory statistics included the Mann–Whitney U test for quantitative data and the chi-squared/Fisher exact tests for qualitative data. The primary outcome of the change in body weight was analyzed using a covariance model (ANCOVA) with the baseline body weight as the covariate and group assignment as the fixed class effect. The changes in body weight from baseline to week 2 and from baseline to week 4 were analyzed while controlling for confounders (estimated mean change expressed as the 90% confidence interval). The efficiency and safety of the outcome were analyzed with a mixed model for repeated measurements. The mixed model included the baseline value (day 1) of the results as the covariate and the two groups (HE-LPF and control) and the visit times (week 2 and week 4) as the fixed class effects. The covariance pattern was assumed to be unstructured but the same for both groups. A
p-value of <0.05 was considered statistically significant. All data analyses were performed using IBM
® SPSS
® version 22.0 (International Business Machines Corp., New York, NY, USA).
4. Discussion
We evaluated the impact of low-protein renal ONSs as either a complete or a partial meal replacement designed for the dietary management of pre-dialysis CKD patients after four weeks. The main endpoint of efficacy was the change in body weight and other parameters regarding nutritional status, including BMI, body composition, waist circumference, and hand strength; none showed any significant differences between the two groups (ITT and PP populations). In the analysis of 3-day food records, the ITT population showed a significant reduction in the energy percentage obtained from protein. Concurrently, the ITT population showed a significant increase in the energy percentage obtained from fat, including SFAs, MUFAs, and EPA, while the mineral intake remained unchanged. Meanwhile, the PP population experienced a similar result and an increase in energy intake (kcal/kg/day). Recently, a systematic review indicated that a low-protein diet might delay the progression of renal function; however, concomitantly, it may increase the risk of malnutrition, as demonstrated by the reductions seen in BMI and body weight [
23]. Dietary management in CKD patients is challenging due to multiple food restrictions, low appetite frequency, or other symptoms that negatively impact nutrient intake and assimilation [
5,
24]. According to our findings, the HE-LPF intervention increased energy intake, decreased protein intake, and did not worsen nutritional status.
Safety endpoints did not exhibit any changes in biochemical markers. Renal function was maintained and was not significantly different between the two groups. This result may be explained by considering the impact of weight on serum creatinine levels [
25]. While the two groups did not display significant differences in body weight at either baseline or after four weeks, it is noteworthy that the HE-LPF group consistently maintained a lower body weight. Although statistically significant results were not observed, this disparity may impact creatinine levels. Additionally, implementing a low-protein diet in individuals with a BMI below 18 presents specific challenges, primarily due to the heightened risk of protein–energy wasting [
5]. Furthermore, there is a lack of substantial randomized controlled trials implementing low-protein diets in populations with obesity, i.e., where BMI exceeds 30 [
26]. Consequently, we excluded individuals with a BMI below 18 and those with a BMI exceeding 30 from the study to reduce potential biases.
Furthermore, implementing an LPD may increase fat and carbohydrate intake, possibly affecting glycemic control or lipid profile metabolic markers. The results of metabolic markers remained stable, presumably due to either the favorable fatty acid profile or the replacement of the protein-rich foods using an HE-LPF as an interventional ONS. In our study, the analysis of the 3 day food records showed that the intake of MUFAs and EPA increased, as did that of SFAs. Evidence suggests that a MUFA-rich diet is beneficial in regulating fat oxidation, weight maintenance, and cholesterol metabolism [
27]. A 13 article meta-analysis indicated that rich omega-3 fatty acids significantly decreased cardiometabolic parameters, including cholesterol and triglycerides [
28]. In the 24 h urine analysis, while no statistically significant difference was observed between the two groups, we noticed a trend in the HE-LPF group toward decreased proteinuria after four weeks. Recent reports have suggested that pharmacological treatments, in synergy with dietary modifications, can enhance the care of CKD patients. For example, a protein-restricted diet has been shown to have an anti-proteinuric effect that complements ACE inhibitors or ARBs [
29]. In our study, blood pressure medication remained unchanged, and there appeared to be a decreasing trend in proteinuria. This may suggest some benefit of the combined reduction in protein intake due to ONS application in the HE-LPF group, along with medication.
Adherence to the investigational product was perfect, with only a slight reduction in the last two weeks of the study compared to the first 2 week period. This result is also promising for applications in clinical practice. Uremic symptoms in CKD patients, particularly those not dialyzed, elicit taste changes and reduced food appeal [
24]. This clinical reality may impact the usual food for this patient population, making ONSs a feasible nutritional management tool. In addition to high adherence to the prescribed units of the ONSs, reports of adverse effects from patients were low overall (less than 10%), mild to moderate in severity, and gastrointestinal (nausea and constipation) in nature. Gastrointestinal symptoms are a factor known to impair the provision of ONSs in CKD patients, with occurrences of nausea and constipation considered typical in uremic pre-dialysis patients [
30]. Therefore, these adverse events are difficult to interpret. This is particularly pertinent since the same events occurred in both groups, suggesting that such symptoms may be related to the progression of CKD rather than the ONSs used.
There were several limitations to this study. First, the current study may have been too short in its relative duration and could not improve nutritional status. Previous studies have reported that body weight and BMI using renal-specific ONSs for six months were enhanced in patients with advanced CKD [
31]. The ability to significantly increase energy intake to the extent that anthropometric indicators are also improved may take time in patients with end-stage renal disease who are at risk of PEW. Second, the study did not find a significant change between the two groups regarding body composition. However, it is worth noting that past research has suggested a potential underlying association between physical activity, especially exercise training, and nutritional supplementation, leading to increased muscle mass [
32]. While we did not observe significant changes in body composition in this study, we cannot rule out the possibility of future research exploring the interplay between exercise training and nutritional supplementation, particularly in influencing muscle quality. Third, the subjects were instructed to implement a low-protein diet before being enrolled. This may have caused a risk of bias regarding the study procedures, which may explain why no significant differences were seen in the Maroni equation. Additionally, this study was conducted in a single center and may not be fully generalizable for other populations. Future research involving HE-LPF application with recruitment in multiple centers should still be conducted, including a long-term follow-up period and an exploration of the impact of physical activity.