Our study tested the potential of a combination of protein and omega-3 supplementation to improve nutritional and inflammatory markers in chronic hemodialysis patients. To increase compliance the supplements were administered during patients’ routine dialysis session, three times per week (“directly observed treatment”). Directly observed treatment allowed for two-thirds of the subjects to receive more than 80% of the stated overall dose over a 6-month period. While compliance was excellent in patients who came in for regular dialysis sessions, the significant comorbidities within this patient population resulted in a large number of missed dialysis treatments (and hence missed supplementation).
We observed that serum albumin, one of the markers of nutritional status, was not improved significantly in either group following the intervention. This finding was in contrast to what has been reported in previous studies.4
This may be explained by the fact that only a small number of patients were able to take all of the supplements provided to them (no missing days) during the study course (n = 21, 33.3%). Patients missed days of supplementation mostly due to frequent hospitalization or because they failed to show up for their routine dialysis treatment, ranging from 1–44 days. Therefore, this could potentially upset the effect of omega-3 and protein supplementation per se. Further analysis on a pool of patients who substantially completed the supplementation course (ie, taking >80% of the supplements) showed marginal improvement in serum albumin at month-6 compared to baseline (3.6 ± 0.3 g/dL versus 3.7 ± 0.3 g/dL, P
= 0.079) but no improvements were noted in those who took <80% of the supplements (3.7 ± 0.2 vs 3.7 ± 0.4, P
= 0.939). Interestingly, nPNA, an indicator of protein intake, remained constant in both groups despite protein supplementation. A similar study by Moretti et al26
also noted a similar trend, in which there were no changes in nPCR despite improvement in serum albumin in the protein group for the second 6 months.
Reduced protein intake and an increase in inflammatory response are two important factors that lead to a decrease in serum albumin.27
However, Kaysen et al28
had noted that low serum albumin in dialysis patients may be attributed to systemic inflammation rather than nutritional inadequacy as a causative factor per se. In relation to this, we also observed a significant inverse correlation between serum albumin and CRP which may indicate the influence of an inflammatory process on serum albumin levels. Friedman and Fadem29
suggested that serum albumin should be taken as a marker of illnesses rather than nutrition. This is due to the fact that serum albumin has a strong ability to predict mortality but rather limited prediction for nutritional status due to significant influence of non-nutrition causes (such as inflammation).
Many of the omega-3 fatty acid supplementation studies in dialysis patients have described various potential outcomes such as attenuating dyslipidemia, inflammation, and providing a cardioprotective effect. Moreover, there is substantial evidence for reducing TAG levels30
even at a dosage as low as 1.5 g/day.33
As for plasma TAG, we saw a tendency for a reduction in TAG levels in both groups although in the omega-3 group statistical significance was marginal (P
= 0.064). The large variation in the difference in TAG changes observed in the placebo group (−7 ± 61 mg/dL, P
= 0.56, ) could be attributed to one subject with very high triglyceride concentrations. Upon removal of this subject the difference in TAG levels between the 6-month and baseline value was 1 ± 44 mg/dL, P
= 0.89. Thus collectively these data suggest no change in TAG levels over 6 months in the placebo group, while there was a tendency for a reduction in TAG levels in the omega-3 group (−20 ± 44 mg/dL, P
= 0.064). Previous studies18
which administered a higher amount of omega-3 per week, with varying percentages of EPA/DHA but with a shorter duration (4–8 weeks), also reported no changes in TAG levels. However, Bouzidi et al reported that a supplementation of 2.1 g omega-3 daily for 3 months among chronic kidney disease patients reduced TAG levels by 48%.35
However, it is important to note that the baseline TAG levels in their study were much higher than the current study (275 ± 58 mg/dL versus 123 ± 60 mg/dL in the omega-3 group). We postulate that, the baseline TAG levels (omega-3 group: 123 ± 60 mg/dL; placebo group: 104 ± 69 mg/dL) were within the normal levels and thus may not have been sufficiently elevated to achieve a significant reduction. Skulas-Ray et al reported that the extent of TAG lowering with omega-3 is a function of baseline TAG levels.36
Omega-3 supplementation resulted in better improvement in LDL-C/HDL-C ratios as compared to placebo which appeared to be due to a greater improvement in non-HDL-C. As for inflammatory markers, our results for CRP were inconclusive. While mean values in the placebo group increased over the 6-month period, this was not the case in the omega-3 group, in which CRP levels stayed the same. Thus omega-3, if not effective in attenuating inflammation, may be beneficial in preventing further increases in inflammatory status. However when the data were evaluated using median CRP values, these differences were no longer apparent suggesting the need for a larger sample size to definitively resolve this issue. Only a small number of studies have investigated the effects of omega-3 on inflammatory markers in hemodialysis patients. It is important to note that most of these studies are not comparable due to differences in study design, supplement dosage, EPA/DHA ratios and study duration. Saifullah et al showed that a supplementation of 1.3 g of oral EPA and DHA daily over a period of 3 months could modestly reduce CRP levels.37
However, a recent study using a larger dosage (2.08 g/day) but a shorter duration (10 weeks) showed no effects on serum systemic inflammatory markers (CRP, interleukin-6, tumor necrosis factor-α) and oxidative stress (malondialdehyde, total antioxidant capacity).38
In a prospective cohort study by Noori et al, the authors showed that a lower omega-6 to omega-3 ratio (~6) was associated with decreased inflammation and overall mortality in hemodialysis patients which indicates the importance of n-6/3 polyunsaturated fatty acid ratios in the diet.13
However, our study was not designed to investigate the effects of this ratio per se.
NFκB, a key player in pathogenesis of inflammation, is stimulated by pro-inflammatory agents such as cytokines and CRP. Studies have shown that NFκB activation and subsequent activation of mononuclear cells triggers a process that causes myocardial inflammatory damage in hemodialysis patients.39
Interestingly, our data for translocation of activated NFκB to the nucleus showed no significant changes following the intervention within and between both groups even though we saw an increase in CRP levels in the placebo group. The latter may have been due to the fact that the baseline CRP values in the placebo group were lower than those assigned to the omega-3 group.
We were restricted in our patient population to one dialysis clinic for this pilot study. While the lipid data suggested benefits of omega-3, the data for inflammatory markers was less clear cut. One plausible explanation for variation in inflammatory markers in the current study may be related to insufficient dosage/frequency of omega-3 supplementation as well as compliance (due to frequent hospitalization resulting in subjects missing dialysis sessions and therefore supplementation). There are several similar studies which also failed to report significant changes in inflammatory markers.18
Studies which demonstrated a significant effect of omega-3 supplementation on inflammation indices are those with a higher dosage and more frequent administration of the supplement (9.1 to 21 g/week versus 7.2 g/week DHA + EPA in the current study) as well as reported higher patient compliance.17
Another factor that could potentially explain the contradictory finding in our study with those studies is baseline levels of inflammatory markers. Omega-3 supplementation appears to be more effective in studies reporting higher baseline CRP (>13.8 mg/dL) than those that did not.17
Notwithstanding some of the limitations discussed above, ours is one of the few studies to report on the use of “directly observed treatment” of oral nutritional supplementation with protein and omega-3 in a cohort of hemodialysis patients. Our results suggest that “directly observed treatment” is technically feasible in hemodialysis patients and does not disrupt the normal dialysis schedule. The relatively large number of missed dialysis sessions due to hospitalizations, however, suggests that “directly observed treatment” should be used in the setting of both outpatient and inpatient dialysis sessions in order to optimize compliance. In addition, while emphasizing the huge progressive inflammatory burden in hemodialysis patients over time; this pilot study suggests that “directly observed treatment” with a combination of omega-3 and protein-based supplement (as opposed to a pure protein supplement) could have some beneficial effects on lipid profile and CRP progression. Further studies using a combination of outpatient and inpatient “directly observed treatment” of fish oil based nutritional supplementation are warranted.