Malnutrition, or protein-energy wasting (PEW), is highly prevalent among patients with chronic kidney disease (CKD), especially those undergoing hemodialysis, and is associated with significant morbidity and mortality. The etiology of malnutrition is multifactorial and includes decreased protein-calorie intake due to anorexia and dietary restrictions, inflammation, hypercatabolism, protein loss during dialysis, metabolic acidosis, uremic toxicity, and the presence of comorbidities (1–4). For this reason, it is recommended to evaluate periodically the appetite, dietary intake, and biochemical data, as well as to carry out a nutritional and functional (morphofunctional) assessment and an individualized approach to the diet of patients by expert professionals. When dietary advice is insufficient to achieve protein-calorie intake goals, the use of oral nutritional supplements (ONSs) is the next step to prevent and/or treat malnutrition (1, 3). The use of ONS (standard or specific for CKD) in patients with hemodialysis has shown, in some randomized studies (compared to usual follow-up), that it can increase protein-calorie intake, weight, fat-free mass (FFM), and fat and albumin concentrations, without raising the levels of electrolytes such as phosphorus or potassium (1–9). Furthermore, in retrospective studies, it has been observed that it could reduce hospital admissions and even mortality (10–12). In these patients, mechanisms of inflammation coexist with oxidative stress, which favors cardiovascular complications that could be attenuated with dietary and pharmacological interventions (13).

The Mediterranean diet has been proposed as the dietary pattern of choice for patients with CKD, which could improve endothelial function, inflammation, oxidative stress, and lipid profile, as well as reduce cardiovascular disease incidence (1, 4, 14). Some of its essential components are virgin olive oil, fish (as a source of n-3 fatty acids), and fiber from plant foods. Virgin olive oil is rich in polyphenols, and its consumption has been associated with a decrease in cardiovascular events, diabetes, and other chronic diseases (15). In hemodialysis patients with CKD, the minor polar compounds of extra virgin olive oil seem to exert an antioxidant and anti-inflammatory effect (16). The use of n-3 fatty acid supplements in patients with CKD could decrease markers of inflammation and oxidation (associated with lean mass depletion) (17). The metabolic alterations inherent to uremia and the intake of a Western-type diet could promote intestinal dysbiosis among patients with CKD and may play a key role in disease progression and complications. Dietary patterns such as the Mediterranean could reduce inflammatory processes, including leaky gut and subsequent endotoxemia (18).

In addition, the use of pre- and pro-biotics could have a crucial role in the regulation of the immune system and prevent infectious complications, treat hyperphosphatemia, reduce the levels of solutes that contribute to the uremic syndrome, as well as improve the lipid profile, oxidative stress, and systemic inflammation (19). Although some studies have shown some beneficial results, there is no conclusive rationale for recommending biotic supplements for improving outcomes in patients with CKD (20).

Whey proteins are rich in branched-chain amino acids, leucine, glutamine, and cysteine and are quickly digested; moreover, they favor a greater protein anabolic response than other protein sources. Although this requires still further evidence (21), its use in hemodialysis patients could reduce inflammatory parameters and improve physical function (22–24).

Recently, a new ONS was developed in Spain specifically designed for malnourished (or at risk) hemodialysis patients with a “similar to the Mediterranean diet” pattern (made up of functional nutrients such as extra virgin olive oil, n-3 fatty acids, whey protein, fiber, and antioxidants) that could improve the achievement of dietary as well as nutritional and functional status goals, metabolic changes, and associated inflammation and oxidative stress.

We aimed to study whether the new ONS, associated with probiotics or not, may improve nutritional and functional status and reduce biomarkers of inflammation and oxidation in malnourished hemodialysis patients, compared to individualized diet recommendations.

From the 220 subjects assessed for eligibility, 59 were randomized. Notably, 31 patients completed the 6-months trial and were analyzed (11 C group, 10 SU-PL, and 10 SU-PR) (Figure 1). The causes for consent withdrawal were in the C group, not wanting to continue with visits and individualized diet (n = 4), difficulties in follow-up due to the SARS-CoV-2 pandemic (n = 2), and the decision of their nephrologist (n = 1); in the SU-PL group, transfer to another facility (n = 1), not wanting to continue with visits (n = 2), difficulties in follow-up due to the SARS-CoV-2 pandemic (n = 2), and lack of supplement acceptance (n = 3); and in the SU-PR group, not wanting to continue with visits (n = 2), difficulties in follow-up due to the SARS-CoV-2 pandemic (n = 1), and lack of supplement acceptance (n = 3). The mean intake of supplements during the 6 months of follow-up was 1.5 ± 0.46 in the SU-PL group and 1.55 ± 0.41 in the SU-PR group. There were no significant differences in the digestive symptoms scale between groups (C, SUP-PL, SUP-PR), neither at baseline nor at any of the 6 months of follow-up (Supplementary Table 1). Supplement acceptance was high (Supplementary Table 2). There was no patient withdrawal due to gastrointestinal side effects. We observed no significant changes regarding gastrointestinal symptoms in patients quitting the study due to consent withdrawal or severe adverse effects (death, admission for transplant) and those who continued in the trial.

There were no basal significant differences between groups regarding age, sex, diabetes, Charlson comorbidity index, or intake of fermented milk or antibiotics during the month prior to inclusion (Table 2). Moreover, there were no baseline differences in any of the parameters for the morphofunctional nutritional assessment, dietary intake, biochemical data, or analyzed biomarkers (except for IL-12) (Tables 3–6).

In this study, we have observed that supplementation with a new ONS specifically designed for malnourished subjects with CKD on hemodialysis improves dietary intake and nutritional status, as well as some biomarkers of inflammation and oxidation, compared to a group on individualized treatment.

In the groups on ONS, we observed an increase in the total caloric (approximately 250 kcal mean), protein (12 g mean), fat (including n-3 fatty acids), and fiber intake, as well as a decrease in glycemic index and an improvement in adherence to the Mediterranean diet pattern. The purpose of the use of ONS should always be complementing, and never substituting, the intake of natural food. In this study, the addition of ONS to the patients’ regular diet helped to achieve the intake recommended in clinical guidelines (1). The increase in energetic intake due to the use of renal-specific protein-energy ONS has also been observed in other randomized studies in patients receiving maintenance hemodialysis (MHD) (7, 28), but not in all of them (1, 5). The new Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline for nutrition in CKD recommended, for patients on MHD who are metabolically stable, prescribing a dietary protein intake of 1.0–1.2 g/kg body weight per day to maintain a stable nutritional status. Nevertheless, in malnourished (or at-risk) patients with PEW, the recommended intake could be higher (3). In previous randomized studies, no increase in protein intake due to protein-energy supplements had been found (5, 7, 29, 30), although the isolated use of some protein-based supplements did help to achieve an increase (21, 31, 32). The main protein intake in supplemented patients in this study increased to over 1.2 g per kg body weight after the intervention, which, together with the fact that half of the protein in the ONS comes from whey protein, may have contributed to the improvement in body composition we observed. The KDOKI guidelines do not routinely recommend supplementation with n-3 polyunsaturated fatty acids (PUFAs) in order to reduce the risk of mortality or cardiovascular events, although they may be prescribed at pharmacological doses to improve lipid profile. In some studies, the use of n-3 fatty acid supplements in patients with CKD seems to decrease inflammatory and oxidation markers (associated with FFM depletion) (17). In our sample, supplemented patients increased their intake of n-3 PUFA, which may have also contributed to the decrease in biomarkers of inflammation and oxidation. In patients randomized to ONS, there was also a higher intake of fiber and a lower glycemic index; moreover, the score in PREDIMED at 6 months was also higher. All these changes may have improved body composition through different anti-inflammatory and antioxidant mechanisms (4, 14, 16, 18, 33).

Malnutrition in patients with MHD is characterized by changes in body composition, especially a decrease in FFM and muscle strength, and it is associated with high morbidity and mortality (34, 35). In our study, patients taking supplements improved their body composition, with a mean increase of 2.6 kg in dry weight, from which 1.5 kg were FFM. These data are similar to those observed in other clinical trials with energy-based and/or protein-based ONS (1, 22, 29, 36). The increase in only fat mass found in other trials with ONS may not be beneficial for this population as it could increase insulin resistance and systemic inflammation (28). Tomayko et al. demonstrated, after intradialytic supplementation with whey or soy protein, improvements in gait speed and shuttle walk test performance (22); however, in the IHOPE study that combined whey protein + exercise, no significant changes compared to the control group were observed (21). In our study, the increase in FFM was associated with an improvement in hand grip strength only in the SU-PL group, and no changes in functionality, measured by SPPB, were found. Although patients were highly encouraged to perform individualized physical exercise, no supervised specific program was designed to improve the results (37).

The changes described in diet and body composition were associated with an increase in prealbumin that reached significant differences in the groups on ONS at month 3. There was also a non-significant increase in albumin. In other randomized trials comparing the use of protein or energy-protein-based ONS in patients with MHD, there were variable results, with albumin levels tending to increase moderately, especially in malnourished patients compared to control or placebo (1, 9, 36); on the contrary, there were no differences regarding prealbumin (5, 7, 38).

Serum albumin and prealbumin may be considered complementary tools to assess nutritional status and as a predictor of hospitalization and mortality; however, they are influenced by non-nutritional factors, especially the degree of inflammation (1). In our study, we have found significant decreases in several biomarkers of inflammation (BDNF, BMP-2, MCP-1, IL-1-beta, IL-4, and IL-8) in supplemented patients, especially in the group on also probiotics. Apart from being used as a biomarker of inflammation, the BDNF is increased in patients with MHD with sarcopenia and frailty (39, 40), BMP-2 is associated with increased oxidative stress and vascular risk (41), and MCP-1 has been used as a marker of structural kidney damage as well as arteriogenic factor in patients with MHD with cardiovascular disease (42–44). In contrast, there is also an increase in IL-10 levels after 3 months, which behaves as an anti-inflammatory cytokine, and whose decrease is associated with increased morbidity and reduced muscle strength in patients with MHD (45). In other randomized studies, supplementation with energy-protein-based ONS did not produce any change in CRP (7, 21, 22, 28–31, 36) or IL-6 (21, 38) levels; nevertheless, intradialytic supplementation with whey or soy protein reduced serum levels of IL-6 (22).

The SU-PR group reached significant differences over time in several biomarkers such as BDNF, MCP-1, IL-10, and TAC, which suggests that probiotics could synergistically act with other active ingredients of the supplement (virgin olive oil, prebiotic fiber, n-3 PUFA, or whey protein, etc) and with the Mediterranean dietary pattern to improve the proinflammatory and oxidative status, and FFM. Despite more studies being necessary to recommend the use of pre- and probiotics in patients with MHD, they could reduce the levels of solutes that contribute to the uremic syndrome, as well as improve the lipid profile, oxidative stress, and systemic inflammation (19, 20).

All these dietary changes in body composition and biomarkers were produced with no increase in the serum levels of phosphorus or potassium (with a clear tendency of the latter toward reduction and achieving normal values in the supplemented groups), in accordance with other randomized studies (1, 36). We also found vitamin D increases after 3 months, similar to the findings of other recent trials (5). These results suggest that this new ONS (with a low content of these electrolytes) can help to achieve nutritional requirements in these patients.

Interestingly, urea levels increased significantly in the SU-PL group but not in the SU-PR. Urea has recently been proposed as a relevant gut-derived toxin that triggers molecular changes leading to insulin resistance and endothelial dysfunction. In CKD models, probiotics from the genus Bifidobacterium have shown reductions in serum urea nitrogen and other uremic toxins levels (46). It is possible that in our study, the probiotics have contributed to the fact that urea levels do not rise despite the increase in protein intake with ONS.

The main limitation of the study (in part due to the SARS-CoV-2 pandemic and the associated difficulties in completing the patients’ follow-up) is that, although we did reach the planned sample size (more than 17 subjects per group), this may not be enough for some variables if we consider the high dropout rate. Nonetheless, the power for the variables reaching statistical significance was, in all cases, above 80%. Some statistical significances were only observed after adding the two supplemented groups (SU-TOT), which may be due to an additive effect of the SU-PR group but could also be secondary to the increase in n; the first option cannot be tested as there was no control-PR group. Notwithstanding, no patient withdrew from the trial because of gastrointestinal symptoms (which were similar to the C group during all the interventions), and only six because of lack of supplement acceptance (16% of the total number of patients randomized to ONS). These results are similar (or better) to those from other trials in which adherence was low (7, 47). Acceptance regarding the organoleptic characteristics of the supplement was high, which is in part motivated by the possibility of changing the flavor as, although the supplement is presented in vanilla flavor, it is delivered with six additional flavors that can be added to facilitate compliance, acceptance, and individualization. ONS compliance was self-reported, and no biomarker to evaluate intake was used; in this sense, it would have been better to measure the normalized protein catabolic rate (nPCR) to evaluate protein intake. Finally, no data on the acid–base status were collected, and it could have provided useful information.

As strengths of the study, we highlight the fact that it is a randomized clinical trial (double-blind regarding probiotics intake), the follow-up is in the long term (6 months), its multicentric nature, the measurement of multiple parameters (diet, morphofunctional nutritional assessment, biochemical parameters, and biomarkers of inflammation and oxidation), and the comparison with a C group that followed an individualized diet prescribed by registered dietitians.

The new ONS specifically designed for patients with MHD with malnutrition (or at risk) improved caloric-protein intake, nutritional status (especially FFM), and some biomarkers of inflammation and oxidation; the addition of probiotics could act synergistically with the ONS components to improve these biomarkers. This study sets the path for new randomized studies with a higher number of patients and, in the long term, confirms these preliminary results and assesses the efficacy of the new ONS in terms of morbidity.

The data presented in this study are available on reasonable request from the corresponding authors.

The studies involving human participants were reviewed and approved by the Research Ethics Committee provincial of Málaga. The patients/participants provided their written informed consent to participate in this study.

GO contributed to the conceptual design of the research, funding acquisition, and drafted the manuscript. GO, FH, and MP contributed to the interpretation of the data. All authors contributed to the acquisition, analysis of the data, critically revised the manuscript, and agreed to be fully accountable for ensuring the integrity and accuracy of the study.