The Effects of Oral fat Based High-Energy Supplements on Nutritional and Inammatory Status in Maintenance Hemodialysis Patients

Background: Protein-energy wasting (PEW) and inammation have been recognized as two major factors associated with the poor prognosis of patients with maintenance haemodialysis (MHD). The aim of this study was to evaluate the effects of oral fat based high-energy supplements (Fresubin) on malnutrition and inammation in MHD patients. Method: This study was open-label, prospective, nonrandomized and comparative. A total of 47 MHD patients with PEW were randomly assigned into 2 groups: a control group, and a Fresubin treatment group, in which patients received daily diet intake and Fresubin nutrient support 120 mL/d for 80 days. Laboratory data and anthropometric parameters were measured. Result: The results showed that compared with baseline, the level of serum albumin at 80 d in the Fresubin treatment group was signicantly increased (35.4 ± 3.7 vs 38.9 ± 2.9, p = 0.003), while there was no signicant difference in the control group. In addition, the magnitudes of changes in albumin (p = 0.009), serum prealbumin (p = 0.017), and abdominal circumference (p = 0.037) in the Fresubin treatment group were markedly increased compared with those in the control group. There was a downward trend in the inammatory marker hypersensitive C-reactive protein in the Fresubin group (p =0.056), which decreased more dramatically than that in the control group (p = 0.026). Conclusion: Fresubin treatment is well tolerated, and improves malnutrition and inammatory status in MHD patients with PEW.


Introduction
In patients with end-stage renal disease (ESRD), inadequate nutrient energy intake is often observed [1,2].
The term "Protein-energy wasting" (PEW), characterized by declines in body protein mass and energy reserves, is common concept that re ects nutritional status in patients with ESRD [3]. Inadequate protein and energy intake were tightly linked to PEW in maintenance haemodialysis (MHD) patients [4,5]. The HEMO study showed that low values of protein and energy intake were associated with indexes of comorbidity, especially in older patients [4]. Araujo et al demonstrated that energy intake was an independent predictor of 10-year mortality in MHD patients [5]. Growing evidence has indicated that PEW and in ammation contribute to quality of life and high mortality in MHD patients [3,6,7].Therefore, the interventions to ameliorate nutritional status and in ammation are crucial.
Individualized nutritional support, an optimized dialysis regime and the management of comorbidities (e.g., infection, metabolic acidosis, heart failure, and depression) are the most essential methods for managing ESRD [8,9]. The guidelines strong recommended nutritional interventions in MHD patients [10]. However, evidence regarding the effects of oral nutritional supplements (ONS) on the nutritional status of MHD patients is insu cient and inconsistent [11][12][13][14]. Most of the ONS used in previous studies were amino acid or protein-based supplements. Although protein and amino acids supplementation may be effective in improving PEW in MHD patients, the risk for metabolic waste (hyperphosphatemia, hyperureaemia) can be substantial and should be carefully monitored [15][16][17]. Previous prospective cohort studies have suggested that total fat and individual types of fat were related to lower total mortality [18]. However, the effects of oral fat based high-energy supplements on the nutritional status and in ammation of MHD patients was largely unknown. Fresubin is an oral high-energy nutrient solution with a fat content of 53.8 g/100 mL that is rich in polyunsaturated fatty acids (12.5 g/100 mL) and free of phosphorus, potassium and protein. In the present study, we evaluated the effects of Fresubin treatment on nutritional and in ammatory status in MHD patients.

Research participants
This study was open-label, prospective, nonrandomized and comparative. It was performed at an outpatient hemodialysis center in a teaching hospital. Approval from the ethics committees of Zhongda Hospital, Southeast University School of Medicine was obtained before subject recruitment (2019ZDSYLL146-P01).
All patients (>18 y) were treated and received MHD for at least 3 months at our hospital. Patients were undergoing 4-to 4.5-h dialysis sessions 3 times per week. The blood ow rate ranged from 200 to 250 mL/min, and bicarbonate buffer was used. A 3-day diet record (one day of haemodialysis, 2 days of nonhaemodialysis) was used to assess the participant's nutritional intake. According to the PEW diagnostic criteria recommended by the International Society of Renal Nutrition and Metabolism (ISRNM) [19], the inclusion criteria for this study were as follows: 1) serum albumin (Alb) < 38 g/L or serum prealbumin (PA) < 0.3 g/L; 2) body mass index (BMI) < 23 kg/m 2 ; and 3) dietary protein intake (DPI) < 0.8 g/kg/day. Patients had to meet any 2 of the above 3 conditions for inclusion in the study. Exclusion criteria: 1) gastrointestinal bleeding and an inability to eat; 2) serious infection and severe wasting diseases; 3) liver failure and cirrhosis; 4) cancer; 5) acute phase of disease; 6) not signed an informed consent; and 7) incomplete information. The owchart was displayed in Figure 1.
A total of 47 patients were involved in this study from August to December, 2019. They were allocated to 2 groups based on subject preference: 1) control group, in which patients received daily diet intake only; and 2) Fresubin treatment group, in which patients received daily diet intake and Fresubin nutrition support 120 mL/d for 80 days. Fresubin (Fresenius Kabi Deutschland, Germany) was chosen because it was the formulary supplement prescribed to meet the nutritional needs (supplement 600 kcal energy) of patients receiving dialysis. The dosage is 120mL per day, divided into two to three times after meal.

Laboratory data
Blood samples were collected for at least 10-h fast and after an HD session respectively. Biochemical parameters, including haemoglobin (Hb), blood urea nitrogen (BUN), serum creatinine (Scr), Alb, PA, total cholesterol (CHO), triglyceride (TG), serum potassium (K), calcium (Ca), phosphate (P), glucose (Glu), serum ferritin (SF) and hypersensitive C-reactive protein (Hs-CRP), were obtained with routine laboratory methods in clinical laboratory of Zhongda Hospital within 4 hours of blood collection. The adequacy of dialysis (Kt/V) was determined according to the Daugirdas method.

Anthropometric parameter assessment
Anthrometric measurements were obtained after haemodialysis (15 to 30 minutes). BMI was calculated using dry weight. Triceps-skinfold thickness (TSF) was measured using a conventional skinfold calliper with standard techniques, and the mid-arm circumference (MAC) and abdominal circumference (AC) were measured using plastic tape. Grip strength (GS) was measured using the same dynamometer with the hand on the non-stula side. All the above parameters were tested 3 times, and the averages were taken.

Study outcomes
The primary clinical outcome of interest was change in nutritional status (Alb, PA, Hb) over the study period (80 days). The secondary clinical outcomes were in ammatory status, other laboratory markers and anthropometric parameters.

Statistical Analysis
Statistical analyses were performed using SPSS 20.0 software. The data are given as the mean ± SD for normally distributed variables and as the median and interquartile range for non-normally distributed variables. Univariate analyses were performed to compare the differences between two groups. All analyses were two-tailed, and a P value < 0.05 was considered to be statistically signi cant.

Baseline patient characteristics
Our study enrolled 47 participants: 22 in Fresubin treatment group and 25 in control group. Finally, 20 (91%) participants in Fresubin treatment group and 25 (100%) participants in the control group completed 80 days testing and were included in the complete case analyses. 2 participants from treatment group withdrew because they did not like the taste of Fresubin.

Fresubin improves serum Alb levels in MHD patients
After 80 days intervention, the level of Alb was signi cantly increased compared with baseline in the Fresubin treatment group (35.4 ± 3.7 vs 38.9 ± 2.9, p = 0.003), while there was no signi cant difference in the control group (37.0 ± 2.3 vs 37.3 ± 2.6, p = 0.656). The serum PA concentration was much higher after intervention in Fresubin treatment group (0.29 ± 0.08 vs 0.33 ± 0.07, p = 0.095), but the difference was not statistically signi cant. Other biochemical indexes (such as K, Ca, P, CHO and TG) and anthropometric parameters were almost the same compared with baseline in both groups (Table 2). Additionally, as shown in Figure 2, the level of Alb increased signi cantly at 30 days compared with baseline (p = 0.003), and the increase continued until the end of the study (p = 0.003).

Fresubin improves nutritional and in ammatory status in MHD patients
We also compared the change values between the two groups from 0 to 80 days and found that the changes in the biochemical indexes Alb and PA in the Fresubin treatment group were markedly increased compared with those in the control group, and the differences were statistically signi cant (p = 0.009 for Alb, p = 0.017 for PA). We also found a signi cant decrease in the in ammatory marker Hs-CRP in the Fresubin treatment group compared with the change in the control group (p = 0.026). With the improvement of patients' nutritional status, the change in abdominal circumference was also increased in the Fresubin group compared with the control group (p = 0.037) ( Table 3). Table 3 The change values data of patients on Fresubin and control groups from 0 to 80days

Discussion
Among the many risk factors that affect the outcomes of ESRD patients, especially MHD patients, nutritional de ciency plays a major role. The prevalence of malnutrition among MHD patients varies from 30-75% [20,21]. In this study, we evaluated the effects of oral fat based high-energy supplements (Fresubin) on nutritional and in ammatory status in MHD patients. These ndings suggested that Fresubin nutritional support could continuously and effectively improve the nutritional status and in ammation in MHD patients after 80 days intervention.
Inadequate dietary protein and energy intake levels are important causes of PEW in ESRD patients and may be caused by anorexia. Furthermore, there is additional nutritional loss during dialysis, such as amino acids, albumin and some trace elements, in the dialysate and in ammatory stimuli associated with the dialysis procedure [3]. The recommended daily protein and energy requirements for haemodialysis patients are 1.2 g/kg of ideal body weight per day and 30-35 kcal/kg of ideal body weight per day [22]. In fact, in many dialysis patients, the levels of protein and energy intake do not reach the recommended proper goals. The protein and energy intake of these research participants are both insu cient.
The ISRNM proposed 4 main categories to diagnose PEW: biochemical criteria, low body mass, decreased muscle mass and low protein intake [19]. Among biochemical indicators, serum albumin is a consistent indicator for PEW, and low serum albumin is one of the strongest predictors of mortality in MHD patients [9,23]. More importantly, a change in the serum level of Alb over time is associated with alterations in the risk of mortality, in that only a small increase or decrease in serum Alb concentration over a period of time is associated with increased or decreased survival, respectively [24,25]. In this study, we treated patients who had poor nutrition status with an oral high-energy nutrient solution, Fresubin 120 mL/day, for 80 days and found that the level of Alb increased quickly and that the increase continued until the end of the study. Another nutritional marker, PA, also increased in the treatment group, and the difference in the change in PA between the two groups was signi cantly different.
There is an important consideration when we ask patients to improve their dietary intake or provide nutrition support. The potential increase in the intake of several harmful elements, especially phosphorus, is a troublesome clinical problem. Hyperphosphatemia is an independent risk factor for cardiovascular disease and death in patients with CKD [26,27]. Interestingly, the amount of dietary protein is usually correlated with phosphorus content and serum phosphorus concentration in ESRD patients. In adenineinduced CKD rats, a high-phosphorus diet was found to induce systemic in ammation and oxidative stress, resulting in the development of PEW, weight loss and hypoalbuminemia [28]. We need to nd a method of compromise that does not increase phosphorus intake but improves the nutritional status of patients. Some foods with a low P/protein ratio should be suggested. In our test, we used the ONS Fresubin to improve the nutritional status of patients while improving the serum Alb without a signi cant effect on phosphorus. Fresubin treatment also had no effect on other biochemical indexes that we should closely monitor, such as blood lipids, Glu, K and Ca.
In ammation is a major driving force for many uraemic complications, including PEW. Persistent, lowgrade in ammation has been recognized as a component of CKD [28]. Animal studies have shown that infusions of TNF, IL-1, and IL-6 cause increased muscle protein breakdown, resulting in muscle atrophy [29]. Clinical studies have shown that malnutrition, in ammation and atherosclerosis are closely related in patients with ESRD [30]. Our study found that the level of the in ammatory biomarker Hs-CRP tended to decrease after nutritional intervention, and the difference in the change value between the two groups was statistically signi cant. This phenomenon has also been observed in other nutritional interventions [31][32][33].
Anthropometric and body composition parameters are also independent predictors of mortality in haemodialysis patients [34]. Contrary to the general population, many studies in ESRD patients have reported a "reverse epidemiology", where higher BMI is paradoxically associated with better survival, especially among those with a higher muscle mass [35,36]. In our study, only the change value of AC was different between the two groups, with no signi cant differences in other parameters, which may be related to the short intervention time.
Throughout the study period, most patients in the treatment group were able to adhere to daily oral nutrient solution support, 2 patients developed nausea after taking Fresubin and withdrew, and 3 patients developed mild abdominal distension, but it resolved on its own. Fresubin therapy was well tolerated, and no other signi cant adverse reactions were observed.
This study has several limitations. First, the sample size was small. Second, the time interval between the two groups was short, and a longer follow-up period would yield more information.

Conclusion
The oral fat based high-energy supplements (Fresubin) were well tolerated and could effectively improve the nutritional and in ammation status in MHD patients with PEW. Flowchart of study participants for the study.