4. Discussion
In numerous aspects, serum UA appears to be a two-faced marker in health and disease [
34]. In the early stages of renal disease, UA is a risk factor marker for mortality, whereas during peritoneal dialysis treatment, it is a prognostic factor [
35]. However, its role in hemodialysis patients is not very clear; similar than a reverse epidemiology phenomenon (paradoxical relationships between nutritional markers such as increased weight or high serum cholesterol levels that are protective in dialysis patients), could be associated with better satisfactory outcomes [
36,
37]. Regarding general mortality, in a study of 7333 HD patients, hyperuricemia correlated with lower mortality in the multivariate models analysis. Furthermore, UA concentrations correlated positively with nutritional markers such as BMI, nitrogen protein catabolic rate (nPCR) and phosphorus levels [
38]. The latter finding has been attributed to a higher antioxidant capacity in patients with hyperuricemia, since it has been observed that UA protects cell membranes against lipid peroxidation and act like a free radical scavenger [
34]. In children, UA has been proposed as a diagnostic tool for CKD progression, since its levels increased as do the antioxidant capacity, measured in saliva by ferric ion reducing antioxidant (FRAP) assay, according to the severity of CKD [
39]. However, it is worth mentioning that the interplay between hyperuricemia, oxidative damage and nutritional status has not yet been explored.
To our best knowledge, this is the first study that explores the association between UA, nutritional status and antioxidant capacity and oxidative damage in HD patients. Since antioxidants inactivate free radicals through two mechanisms—SET (single electron transfer) or HAT (hydrogen atom transfer)—the antioxidant capacity was evaluated by the DPPH
● scavenging and ORAC assays. ORAC is a HAT-based assay and DPPH radical scavenging is a SET-based assay. We are tempted to speculate that the differences in both assays may explain the fact that only the DPPH
● scavenging ability was significant between normouricemic and hyperuricemic patients. Patients with hyperuricemia had higher antioxidant capacity, as measured by DPPH
● scavenging activity, and less oxidative damage, as measured by MDA. Uric acid plays a role as an antioxidant or oxidant in different clinical scenarios. Although fruits and vegetables have abundant amounts of dietary antioxidants, they cannot adequately represent the overall ability and interactions of antioxidants in the whole diet. For example, in our study we analyzed the consumption of food groups, and the consumption of fruits and vegetables that could have a greater association with antioxidant capacity was only 1.3 servings of fruits (0.7 to 1.9 in hyperuricemic, and 0.8 to 2.2 in normouricemic) and 2 servings of vegetables (1.3 to 3.4 in hyperuricemic, and 1.2 to 2.4 in normouricemic). Thus, the dietary concept which takes the whole dietary antioxidants into account has become more prominent. Dietary total antioxidant capacity (DTAC) is a novel indicator of diet quality [
40], which is used to estimate the cumulative power of antioxidants in the whole diet [
41]. Recently, DTAC is described as an effective tool for determining the health outcomes in populations [
42,
43]. This new approach could serve for future lines of research to understand the behavior and association of uric acid, antioxidant status and diet in these patients [
44].
In respect to our secondary outcomes, Beberashvili et al. [
18,
19] studied geriatric patients to find an association between UA and nutritional status. In contrast, we studied a relatively young population (median age was 40 (29–52) years) and found similar results; in our country, a dialysis registry is lacking but the mean age of people with CKD is 44.8 ± 17.2 years old [
45,
46]. In our population, the main etiology of CKD was unknown, contrary to that described in the studies by Abbas et al. [
47] and Hsu et al. [
48], in which the main causes were diabetic nephropathy and arterial hypertension. We found a prevalence of PEW (score MIS ≥6) of 35%, a low prevalence compared to those usually found in HD patients worldwide, which ranges from 50% [
49] according to MIS, to 52.5% [
50] and 70% [
51] according to ISRNM criteria.
One of the main findings of our study was the existence of clinical and statistically significant differences between hyperuricemia and normouricemia, in the variables of nutritional status according to the logistic regression model between UA and albumin, which appropriately classified 90.3% of the study subjects. No independence was found between UA and other nutritional variables, likely because the nutritional status is a construct made up of different variables (the logistic regression data are not shown).
All patients had similar dialytic characteristics, but patients with hyperuricemia had higher creatinine, predialysis BUN and potassium levels. In patients with normouricemia, the risk of having potassium levels lower than 5 mg/dL was 1.97 times higher than in patients with hyperuricemia. Regarding the biochemical variables of nutritional status, patients with normouricemia had higher concentrations of creatinine and potassium. In the study by Beberashvili et al. [
18], creatinine levels were higher in the third tertile than in the first (8.43 ± 2.2 vs. 6.51 ± 2 mg/dL); the same authors found that albumin levels were also higher in the last tertile (3.9 ± 0.3 vs. 3.7 ± 0.4,
p < 0.001), although no significant differences were found in our study.
Some variables (biochemical parameters such as phosphorus, albumin, hemoglobin, transferrin levels and anthropometric parameters such as BMI, arm circumference, triceps skinfold and percentage of body fat) were similar between both study groups, which could explain why no differences were observed in the final score or in the diagnosis of PEW between patients. In the cohort of dialysis patients studied by Bae et al. [
22], UA levels <5.5. mg/dL were associated with overall mortality (adjusted HR of 1.720; 95% CI, 1007–2937,
p = 0.047); there was also a positive correlation between UA levels <5.5 mg/dL and nutritional factors such as BMI (regression coefficient [B] = 0.042;
p = 0.091), Subjective Global Assessment (SGA) (B = −0.062,
p = 0.014), serum phosphorus (B = 0.107,
p < 0.001) and albumin (B = 0.127,
p < 0.001). Among patients with low levels of UA (<5.5 mg/dL), there was a higher proportion of malnourished subjects, according to SGA score, lower BMI and lower concentrations of total proteins, phosphorus and serum albumin. In the study by Beberashvili et al. [
18], mean MIS score was lower in the hyperuricemia group (5.06 ± 3.1 mg/dL) than in the normouricemia group (7.44 ± 3.5 mg/dL) (
p < 0.001). In contrast, in our study we did not find differences between the scores of the groups classified according to UA levels. Although hyperuricemia was not statistically significant in the logistic regression models used in our study for some markers of nutritional status, including it in the model did not decrease the value of R
2 or the percentage of patients it was able to accurately classify (the model explained 48.6% of the PEW and accurately classified 80.6% of the population).
In our study, handgrip strength values were very similar between both groups of subjects, which could be associated with the fairly similar prevalence of PEW among the population. Other studies found that low muscle strength, as measured by dynamometry, was associated with PEW and was considered a nutritional marker associated with muscle loss [
52]. Some studies have even found a positive correlation (r = 0.26;
p < 0.001) between handgrip strength and UA levels [
18].
In contrast, the analysis of body composition by BIVA revealed differences in dielectric properties; patients with hyperuricemia had higher values of R/H and Xc/H than patients with normouricemia, indicating better body cell mass and lower volume overload. The risk that patients with normouricemia would have a ratio of Xc/H lower than 35 Ω/m (worse body cell mass) was 1.8 times greater than that for patients with hyperuricemia. Few studies have analyzed the BIVA values of patients on HD and their relationship with UA; most have analyzed only total body water, extracellular water, fat mass and fat-free mass values. One of the indicators of BIVA with the highest prognostic value in patients on HD is the PA, which has been demonstrated to have an inverse relationship with mortality (the greater the PA is, the lower the risk of mortality); for example, studying a cohort of 91 patients on HD, Beberashvili et al. [
53] reported that for each 1° increase in PA, the crude and adjusted mortality HR were 0.6 (95% CI 0.54–0.71) and 0.61 (95% CI 0.53–0.71), respectively. In the present study, PA values were higher in patients with hyperuricemia than in those with normouricemia.
Furthermore, cachexia (the most severe form of malnutrition in dialysis patients) was lower in patients with hyperuricemia. In our study the risk that patients with normouricemia would have a PA lower than 5.5° was 2.28 times higher than that for patients with hyperuricemia; the risk of having cachexia, diagnosed by bioelectrical impedance vector analysis, according to Piccoli et al. [
32] was 1.9 times higher.
Figure 1 shows that the ellipse of patients with normouricemia is within the range of cachexia and volume overload, while patients with hyperuricemia had better nutritional and hydration status. There are no studies that use impedance vectors as variables of nutritional and hydration status and analyze their association with UA levels.
In addition to the changes induced by CKD in the metabolism of UA, dietary and pharmacological interventions, as well as the nature and extent of dialysis treatments, greatly modify the concentration of UA in the population with CKD. The intake of kilocalories consumed per day was the same in both groups, both in kilocalories/kg of actual and ideal weight. For proteins, contrary to what the dietary restrictions in the intake of purines for patients with hyperuricemia have led us to expect, patients had a higher protein intake as measured by grams of protein/kg of ideal weight and intake of protein of animal origin.
It has been widely described in the literature that the caloric and protein intake of HD patients is below the recommendations of the KDIGO guidelines (30 to 35 kcals/kg/d and 1.2 g/d of calories and proteins, respectively). The reported average caloric intake has ranged from 23.9 ± 7.01 to 24.8 ± 7.5 kcals/d, while the average protein intake has ranged from 0.98 ± 0.30 to 1.1 ± 0.4 g/d. Luis et al. [
6] reported that only 11% and 41% of patients on HD meet the caloric and protein intake requirements, respectively. The nPNA, a more specific indicator of protein intake, was higher in patients with hyperuricemia. Beberashvili et al. [
18] obtained similar results: 1.10 ± 0.27 vs. 1.00 ± 0.20 in the third and first tertile of UA of their study population, respectively. In our study, the risk that patients with normouricemia would have a nPNA below 1.0 was 2.8 times higher than for patients with hyperuricemia. In contrast with what is true for the general population, low UA levels (but not high UA) are associated with higher mortality from all causes for HD patients, especially when they have a low protein intake. In fact, protein-rich diets tend to contain large amounts of purines, so that the higher concentrations of UA could indicate a better nutritional status in the population with ESRD [
20].
In general, the diet of patients on HD is very low in fruits, vegetables, legumes and dairy products (foods rich in antioxidants in the first two and in proteins in the latter one). In our study, this was true for both groups of patients. Fructose levels, a variable that has been implicated in the increase in UA levels, were not different between groups (data not shown), likely because patients tend to underreport the intake of sugar and high-fructose foods in the food record.
The most important strength of our study is that it includes measurements of antioxidant capacity and oxidative damage. Furthermore, it is possible that a low concentration of UA results in a lower total antioxidant capacity in patients on dialysis, although further research is needed to clarify these mechanisms.
Cohort studies have described a phenomenon of reverse epidemiology on HD patients, where high concentrations of UA are a protective factor against mortality and morbidity. Those studies have separately measured some variables of nutritional status and concluded that high UA levels are an indicator of better nutritional status, as evidenced by the positive association between UA levels and nutritional status variables. Furthermore, low concentrations of UA are considered a consequence of poor protein intake and the presence of malnutrition. Hsu et al. [
48] found a positive correlation (r = 0.518,
p < 0.001) between UA and predialysis BUN (indicator of protein intake), a similar result to that obtained in the present study, where the corresponding values were r = 0.479 and
p < 0.001. This phenomenon of reverse epidemiology has been used to explain an improved antioxidant capacity of UA in vivo and in vitro, where it has contributed up to 60% of the elimination of free radicals in blood serum.
The results obtained in this study should be supported by measuring other markers of oxidative damage (more specific for proteins and DNA) to achieve a better understanding of the underlying mechanisms that promote antioxidant capacity in subjects with hyperuricemia on HD. This would also support the associations and correlations that have been found between hyperuricemia, some parameters of nutritional status and mortality, which have suggested the existence of a phenomenon of reverse epidemiology in HD patients with respect to the role of UA (similar to creatinine, potassium and BMI values in dialysis patients) [
37]. Rethinking UA as a laboratory marker of nutritional status would require changing the dietary guidelines for subjects with hyperuricemia in order to prevent PEW. Establishing the existence of a phenomenon of reverse epidemiology with respect to UA levels in HD patients would require further studies with larger samples.
Limitations: We did not evaluate dietary supplements and drugs consumption except for allopurinol so we cannot analyze the effect of drugs (such as diuretics, angiotensin-converting enzyme inhibitors, statins and fibrates) on UA; however, we did a sub-analysis without including subjects with an allopurinol prescription and the results were similar. Furthermore, we did not register inflammatory markers such as white blood cells and C reactive protein. Finally, it is important to mention that all hemodialysis patients in this study had nutritional advice (AEC trained both dietitians); however, to our best knowledge, the same is not true for all hemodialysis units in our country and could be considered a bias factor in the study.
This research exposes how UA can be an indicator of the nutritional status associated with a greater antioxidant capacity. UA could be used as a marker of nutritional status, together with serum albumin, in environments where there are not enough nutritional resources to identify patients with nutritional risk in an inexpensive, easy and simple way.