Elsevier

Clinical Nutrition

Volume 35, Issue 2, April 2016, Pages 331-336
Clinical Nutrition

Randomized control trials
A randomized controlled trial of the effects of n-3 fatty acids on resolvins in chronic kidney disease

https://doi.org/10.1016/j.clnu.2015.04.004Get rights and content

Summary

Background and objective

The high incidence of cardiovascular disease (CVD) in chronic kidney disease (CKD) is related partially to chronic inflammation. n-3 Fatty acids have been shown to have anti-inflammatory effects and to reduce the risk of CVD. Specialized Proresolving Lipid Mediators (SPMs) derived from the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) actively promote the resolution of inflammation. This study evaluates the effects of n-3 fatty acid supplementation on plasma SPMs in patients with CKD.

Methods

In a double-blind, placebo-controlled intervention of factorial design, 85 patients were randomized to either n-3 fatty acids (4 g), Coenzyme Q10 (CoQ) (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. The SPMs 18-HEPE, 17-HDHA, RvD1, 17R-RvD1, and RvD2, were measured in plasma by liquid chromatography–tandem mass spectrometry before and after intervention.

Results

Seventy four patients completed the 8 weeks intervention. n-3 Fatty acids but not CoQ significantly increased (P < 0.0001) plasma levels of 18-HEPE and 17-HDHA, the upstream precursors to the E- and D-series resolvins, respectively. RvD1 was significantly increased (P = 0.036) after n-3 fatty acids, but no change was seen in other SPMs. In regression analysis the increase in 18-HEPE and 17-HDHA after n-3 fatty acids was significantly predicted by the change in platelet EPA and DHA, respectively.

Conclusion

SPMs are increased after 8 weeks n-3 fatty acid supplementation in patients with CKD. This may have important implications for limiting ongoing low grade inflammation in CKD.

Introduction

Individuals with chronic kidney disease (CKD) have up to a 10–20 fold greater risk of cardiac death than age and sex-matched controls [1]. CKD is associated with significant patient morbidity and mortality and the treatment of CKD by dialysis makes a large contribution to the growing health care costs. More than 50% of deaths in stage 5 CKD patients receiving maintenance dialysis are due to cardiovascular disease (CVD), and the risk of coronary artery disease increases exponentially with declining kidney function [2], [3]. In the National Health and Nutrition Examination Survey (NHANES II), renal function of less than 70 ml/min/1.73 m2 associated with a 51% increase in CVD death risk [4], while the Atherosclerosis Risk in Communities Study [5] showed that GFR >15 and <59 ml/min/1.73 m2 associated with a 38% increase in risk of CVD death. The increased incidence of CVD in CKD is explained in part, by an increased prevalence of traditional risk factors such as hypertension, diabetes mellitus, dyslipidemia, smoking, obesity and physical inactivity, and non-traditional risk factors including anemia, abnormal calcium/phosphate metabolism, inflammation, malnutrition, oxidative stress, and elevated lipoprotein (a) [1]. CKD is now considered a risk factor for all-cause mortality independent of CVD risk [2], [3], [6], [7].

Inflammation plays an important role in acute and chronic kidney injury and may contribute to glomerular and tubulointerstitial damage. Unresolved inflammation promotes progressive glomerulosclerosis and interstitial fibrosis manifest as proteinuria and eventual renal failure [8], [9]. Resolution of inflammation is an active process regulated by novel autacoids known as Specialized Proresolving Lipid Mediators (SPMs) [10], [11]. SPMs are generated locally by polymorphonuclear leukocytes during the resolution of inflammation and include lipoxins derived from the n-6 fatty acid arachidonic acid (AA, 20:4n-6), and resolvins, protectins and maresins derived from the n-3 fatty acids eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) [10]. Several families of chemically and functionally distinct SPMs have been identified including E-series resolvins derived from EPA via P450 metabolism or aspirin-acetylated cyclooxygenase (COX-2), and D-series resolvins, protectins/neuroprotectins and maresins derived from DHA via lipoxygenase or aspirin acetylated COX-2 [11]. SPMs act at picogram-nanogram concentrations in vivo and directly block and limit excessive polymorphonuclear leukocyte chemotaxis. They inhibit pro-inflammatory cytokine production, increase anti-inflammatory cytokine synthesis, and activate specific G-coupled protein receptors on neutrophils and macrophages to enhance clearance of cellular debris that is required for tissue homeostasis to be re-established [11], [12].

n-3 fatty acids have been associated with cardiovascular protection and improve cardiovascular disease risk factors such as blood pressure, plasma triglycerides and inflammation [13], [14]. We have also shown that n-3 fatty acid supplementation results in elevated levels of SPMs in healthy volunteers [15], [16] suggesting that they may contribute to altered immune function. In a randomized controlled trial that examined the main and additive effects of n-3 fatty acids and coenzyme Q10 (CoQ) on cardiovascular risk in patients with CKD we showed that n-3 fatty acid supplementation reduced blood pressure, heart rate and plasma triglycerides [17]. As there is no evidence to suggest that CoQ affects SPM, this study utilized plasma samples from that trial [17] to assess how n-3 fatty acid supplementation affected plasma SPM using a main effects analysis.

Section snippets

Study population

Men and women with chronic renal impairment, aged 25–75 years, were recruited from the renal units of Royal Perth, Sir Charles Gairdner and Fremantle Hospitals, in Perth, Western Australia. All participants had estimated (e) GFR >15 and <60 ml/min/1.73 m2, and serum creatinine <350 mmol/l [18]. Patients were current nonsmokers and were excluded if they had angina pectoris; major surgery; a cardiovascular event or diagnosis of CVD; BP >170/100 mmHg; diabetes; liver disease; nephrotic syndrome

Patient characteristics

The CONSORT diagram for the study has been previously published, Mori et al. [17]. At baseline there were 63 men and 22 women aged 56.5 ± 1.4 years with a BMI of 27.3 ± 0.5 kg/m2 and clinic BP of 125.0 ± 1.7/72.3 ± 0.9 mmHg. Mean eGFR was 35.8 ± 1.2 ml/min/1.73 m2 (range 17.3–58.1 ml/min/1.73 m2) (stages 3–4 CKD) [18]. Baseline characteristics (Table 1) of the 74 patients that completed the trial (54 men and 20 women) confirmed the groups were well matched [17].

Effects of n-3 fatty acids on platelet phospholipid fatty acids

Baseline platelet phospholipid

Discussion

Our study has shown for the first time that supplementing patients with CKD for 8 weeks with 4 g/d of n-3 fatty acids enhances the synthesis of SPMs that promote resolution of inflammation. This finding may have important implications related to limiting ongoing low grade inflammation in CKD. The study showed that n-3 fatty acids significantly increased RvD1 and the upstream precursors of the E-series and D-series resolvins, 18-HEPE and 17-HDHA, respectively. RvD2 and 17R-RvD1 were not

Funding sources

The study was supported by grants from the National Health and Medical Research Council of Australia [APP303151 and APP1010495] and the National Heart Foundation of Australia [G 09P 4280]. Emilie Mas is supported by the Medical Research Foundation of Royal Perth Hospital. Trevor Mori and Rae-Chi Huang are National Health and Medical Research Council of Australia Research Fellows.

Author contributions

Emilie Mas developed the LCMSMS method, analysed samples using mass spectrometry, assisted in the interpretation of the data and writing of the manuscript.

Valerie Burke performed the statistical analyses and contributed to the revision of the manuscript.

Anne Barden contributed to the statistical analysis, interpretation of results and writing of the manuscript.

Ashley B. Irish was involved in the study design, obtaining funding and recruitment of patients, interpretation of results and the

Conflict of interest

None.

Acknowledgments

We thank Jackie Mansour, Christine Cowpland, Noeline Atkins and Lynette McCahon for diet counselling, nursing and technical assistance. We thank the renal physicians from Royal Perth Hospital (Dr Mark Thomas, Dr Barry Saker, Dr Kevin Warr), Fremantle Hospital (Dr Paolo Ferrari, Dr Helen Rhodes, Dr Hemant Kulkarni) and Sir Charles Gairdner Hospital (Dr Brian Hutchison, Dr Neil Boudville, Dr Grant Luxton, Dr Harry Moody, Dr Steven Richards) for their assistance in the recruitment of patients.

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