End-stage kidney disease (ESKD) is a major health burden worldwide, with over 2 million people estimated to be receiving renal replacement therapy [1
]. Among those with ESKD, cardiovascular disease (CVD) accounts for almost 50% of all deaths, most commonly sudden cardiac death [2
]. Many factors are known to influence the elevated CVD risks in ESKD, including high blood pressure, dyslipidaemia and high levels of oxidative stress [3
]. The uraemic state, which causes increased production of pro-inflammatory cytokines and promotes oxidative stress, may trigger the onset and progression of atherosclerosis and CVD [5
]. While adequate dialysis therapy ameliorates the accumulation of uremic toxin and pro-inflammatory cytokines, the dialysis process itself can induce a chronic state of inflammation [6
]. This can be further compromised by the loss of key antioxidants during haemodialysis [7
], which further exacerbates inflammation and therefore, increases the risk of CVD in dialysis patients.
Lifestyle modification, including adherence to a cardio-protective diet may provide potential improvements in CVD risk factors in dialysed ESKD patients [8
]. However, common limitations to developing nutrition management plans in dialysis, particularly haemodialysis, arise when attempting to implement a cardio-protective diet [9
]. Many nutrient restrictions placed on haemodialysis patients have the knock-on effect of limiting antioxidant vitamins (e.g., ascorbic acid, tocopherols), minerals (e.g., selenium), and various non-nutritive polyphenols, which may be attributable to the commonly higher levels of potassium in nutrient-rich fruit and vegetables [10
]. Therefore, a low risk dietary intervention which may improve intake of potentially cardioprotective compounds may improve CVD outcomes in the haemodialysis patient.
A healthy dietary pattern, such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diet, are associated with reduced risk of death in renal disease [8
]. One of the proposed mechanisms of mediated risk is through higher intake of fruits and vegetables, which are inherently cardio-protective due to their higher levels of dietary fibre, antioxidants, and lower renal acid load [10
]. In addition, plant-based diets provide an abundant source for a large number of non-nutrient phytochemicals such as carotenoids and polyphenols [12
Polyphenols, present only in plant-based foods, have been associated with reductions in cardiovascular disease and related chronic diseases in large observational studies [14
]. Examples of food sources of polyphenols include various berries (hydroxybenzoic & hydroxycinnamic acids), grapes and currants (anthocyanins), onions and kale (flavonols), parsley and celery (flavones), soy products (isoflavones), and fruit juices (flavanones) [18
]. The potential mechanisms of action responsible for these cardioprotective effects include their antioxidant and anti-inflammatory properties [19
]. Polyphenols may also influence cholesterol levels through modulation of hepatic cholesterol metabolism [20
]. Furthermore, animal studies have demonstrated reductions in blood pressure after polyphenol consumption that was associated with endothelium-dependent relaxation and induction of gene expression related to nitric oxide synthase [21
In haemodialysis supplementation studies, key vitamins have demonstrated improvements in (non-polyphenol) antioxidant activity, such as Vitamin C [22
] and Vitamin E supplementation [23
]. While other polyphenol-rich interventions have shown promise to control oxidative stress and ameliorate inflammation in ESKD patients, for example, grape juice powder [25
], pomegranate juice [26
], turmeric [27
], and cocoa flavanols [28
To date, the effects of polyphenol-rich interventions on CVD risk markers is mixed and no systematic review has specifically evaluated nor pooled the effect of polyphenols on CVD outcomes in dialysis patients. Therefore, the aim of this review was to systematically evaluate the literature from existing randomised controlled trials on polyphenol-rich interventions (food and products) and how it affects CVD markers in haemodialysis populations.
The aim of this systematic literature review was to synthesise results from existing randomized controlled trials to evaluate the effect of polyphenol-rich interventions on cardiovascular markers in haemodialysis patients. The results of individual studies included in this review indicate that polyphenol-rich interventions may improve cardiovascular risk in patients on haemodialysis by improving various markers of inflammation (i.e., CRP, IL-6, TNF-α), lipid profile (i.e., HDL-C and triglycerides), blood pressure, and oxidative stress (i.e., advanced oxidation protein products, polymorphonuclear leukocyte priming, myeloperoxidase, oxidized fibrinogen, catalase, glutathione peroxidase, and MDA); with varying effect sizes and precision across studies.
Despite individual studies reporting significant improvements, pooled results report no effect for most outcomes excepting myeloperoxidase, diastolic blood pressure and triglycerides. Only myeloperoxidase, a measure of oxidative stress, had a large pooled effect size. In addition, using the GRADE assessment, most outcomes were rated as moderate or very low quality which provides limited confidence that the effect sizes reported in the existing evidence is representative of the true effect. The exception is for diastolic blood pressure, which was rated as high quality.
Individual studies that investigated cacao [28
], pomegranate [26
], turmeric [27
], and soy [41
], reported significant improvements in cardiovascular measures. Sensitivity analyses indicate that some polyphenol-rich interventions may provide greater improvements in cardiovascular markers. However, due to the small number of available studies investigating individual interventions in the haemodialysis population, it is premature to conclude superiority of one polyphenol-rich intervention over another at this time. In addition, while polyphenol-rich interventions reported significant improvements in numerous cardiovascular markers, there was little consistency in reported outcomes between studies that measured the same outcome and/or used the same intervention (e.g., blood pressure in [36
]). Hence, future studies are required to expand the currently limited evidence base and to address such limitations.
The low baseline levels of some cardiovascular markers may be a possible explanation for the null findings and/or small effect sizes reported in some included studies and pooled data as it may be unlikely that further reductions are possible. For example, Janiques et al. [25
] reported no significant difference in CRP; however, reported baseline levels (range: 2.6–2.6 mg/dL) were in the normal range (<3 mg/dL). In contrast, Paketrat et al. [38
] reported significant reductions in CRP in participants that had CRP levels above the normal range (range: 7.0–10.8 mg/dL). This is also supported by the results of Wu et al. [44
], Shema-did et al. [36
], and Chen et al. [42
] that reported greater decreases in blood pressure or cholesterol measures in hypertensive or hyperlipidemic participants, respectively.
Due to the large number of foods that contain appreciable levels of polyphenols [30
], the habitual diet of participants may be a significant influence on study results, if not appropriately controlled for. Few studies included in this review implemented measures to control for this; however, future studies may benefit from implementing methods such as recording habitual diet throughout the study through the use of food diaries and research dietitians as well as educating participants on high polyphenol foods to avoid during the trial duration.
Few adverse events (predominantly gastrointestinal complains, one significant bleeding event reported [28
]) were reported during the included trials which provide preliminary evidence for polyphenol-rich interventions being relatively safe within the haemodialysis population. However, due to the additional dietary restrictions present in this population, close monitoring for adverse events are required with clinical use and future trials are required to further evaluate their safety. In particular, although not reported to significantly affect patients in the included studies, consumption of certain polyphenol-rich food items, such as pomegranate juice, can significantly increase potassium intake beyond what would be typically advised for dialysis patients and therefore, care should be taken with people with history of or at higher risks of hyperkalaemia.
A further consideration for future research is to address the poor bioavailability of specific polyphenols. Resveratrol and curcumin (found in turmeric) [45
], for example, have been demonstrated in pharmacokinetic studies to have poor bioavailability and a short half-life which has been addressed in several studies by using various methods such as nanoencapsulation, lipid emulsions, and co-administering active compounds that interact with liver enzymes involved in drug metabolism [46
]. Addressing limitations with bioavailability may provide greater treatment efficacy.
A related research area is to elucidate potential inter-individual differences in polyphenol metabolism as this will inform which patients are likely to benefit from polyphenol-rich interventions. Individual differences in gastrointestinal microbiota appear to significantly influence the metabolism of certain polyphenols [48
]. For example, the soy isoflavone, daidzein, is metabolised to (S)-equol in only 25–60% of the population [49
]. Metabolism of ellagic acid, found in foods such as pomegranate and berries, can also be affected by microbiota composition, affecting timing, quantity, and types of metabolites excreted [50
]. The role of microbiota on polyphenol metabolism in patients with kidney disease may be further complicated due to the possible influence of chronic kidney disease on intestinal microbiota [51
This review includes studies that have used polyphenol-rich interventions. However, food interventions are comprised of several bioactive nutritive (e.g., vitamins and mineral) and non-nutritive compounds (e.g., polyphenols) and therefore, the results of the included studies may have been influenced by these additional compounds. Future trials that use standardized polyphenol extracts are recommended to control for the influence of non-polyphenol compounds.
The findings of this study provide preliminary evidence regarding polyphenol-rich interventions; however, results and conclusions are limited by the heterogeneity of interventions, dosages, and durations as well as variability in the cardiovascular risk of included participants. Although polyphenol-rich interventions have reported benefits in non-ESKD patients, considering the inclusion criteria of this review, generalising results to patients with ESKD or chronic kidney disease who are not receiving dialysis should be avoided until further studies are conducted. Furthermore, studies with large sample sizes are required to sufficiently evaluate the adverse events of polyphenol-rich interventions in this population group.