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© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
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EPHROL
IntroductIon
Patients with chronic kidney disease (CKD), especially tho-
se progressing to end-stage renal disease (ESRD) or un-
dergoing dialysis treatment, are at considerably increased
morbidity and mortality risks (1). Persistent inflammation,
malnutrition and metabolic alterations play an important role
in this excess mortality risk (2-5). Whereas limited evidence
supports the suggestion that reduction in total dietary fat
intake per se can decrease CVD, replacement of dietary
saturated fat and trans-fat with unsaturated fat has been
recommended for prevention of cardiovascular disease
(CVD) in the general population (6). Dietary n-3 polyunsatu-
rated fatty acids (PUFAs) are increasingly gaining attention
in CKD, owing to their broad cardioprotective effects. Ho-
wever, n-3 PUFA is not the only dietary fat with beneficial
effects on health. The purpose of this review is to summa-
rize available evidence regarding implications of dietary fat
modification in CKD patients.
Fatty acIds: general consIderatIons
There are 3 main types of fatty acids in humans: saturated
fatty acids (SFAs), monounsaturated fatty acids (MUFAs)
and PUFA. The last 2 are further classified into n-3, n-6
and n-9 (or omega-3, -6 and -9) subfamilies (7). Fatty acids
have some biological functions: They are the basic building
blocks of lipids; they provide an efficient source of energy,
yielding large quantities of adenosine triphosphate (ATP)
(8, 9); they act as second messengers, amplify or modify
signals to control enzyme activities; and they are involved in
regulating gene expression (10). Some of these effects can
be highly specific to particular fatty acids. In addition, there
abstract
Replacement of dietary saturated fat with unsaturated
fat has been recommended for prevention of cardio-
vascular disease (CVD) in the general population. Less
is known of the health risks in individuals with chronic
kidney disease (CKD), of a diet with an unhealthy fat
profile, in general characterized by insufficient polyun-
saturated fatty acids (PUFA) and excess satu rated
fatty acids (SFA). The dietary intake of PUFA, both
the n-3 and n-6 subfamilies, is increasingly gaining
attention in CKD, owing to its broad cardioprotective
effects. Conversely, dietary SFA may promote CVD in
this vulnerable population. This review discusses the
potential benefits of dietary fat modification in CKD
patients, including plausible effects on renal function,
albuminuria, lipoproteins, nutritional status, inflam-
mation, thrombosis and clinical outcomes. Increasing
evidence supports the concept that n-3 PUFA might
have therapeutic potential in reducing proteinuria in
CKD and reducing triglycerides and inflammation in
dialysis patients. In addition, emerging evidence sug-
gests that linoleic acid, a major n-6 PUFA derived from
vegetable oils, may be beneficial for a number of CVD
risk factors. Increased consumption of oily fish as part
of plant-based diets with low content of SFA is likely
to benefit patients who have CKD, or are at risk of de-
veloping CKD. Such recommendations are in line with
the concept of a healthy “Mediterranean diet” and are
in line with current dietary recommendations for CVD
prevention in the community.
Key words: Cardiovascular disease, Chronic kidney
disease, Dietary fat, End-stage renal disease, Fatty acid
composition, Stearoyl-CoA desaturase-1
1
Divisions of Renal Medicine and Baxter Novum,
Department of Clinical Science, Intervention and
Technology, Karolinska Institutet, Stockholm - Sweden Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm - Sweden Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm - Sweden Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm - Sweden
2
Center for Molecular Medicine, Karolinska Institutet,
Stockholm - Sweden
Xiaoyan Huang 1, Bengt Lindholm 1,
Peter Stenvinkel 1, Juan Jesús Carrero 1,2
Dietary fat modification in patients with chronic
kidney disease: n-3 fatty acids and beyond
REVIEW
DOI: 10.5301/jn.5000284
2© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
Huang et al: Dietary fat modification in CKD
are more dynamic functions of fatty acids – e.g., antiinflam-
mation (11, 12).
Major dietary sources of fatty acids are summarized in
Table I. Linoleic acid (LA; 18:2 n-6) and α-linolenic acid
(ALA; 18:3 n-3) are essential fatty acids that cannot be syn-
thesized endogenously by mammals and therefore must
be derived from the diet. Both eicosapentaenoic acid (EPA;
20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) are
long-chain n-3 PUFAs of marine origin. Although they can
be synthesized from dietary ALA via elongation and de-
saturation endogenously, the efficiency of the conversion
from ALA to EPA is poor and controversial (0.2%-15%),
and the conversion to DHA is even poorer (13, 14). SFA and
MUFA are considered nonessential fatty acids, because
apart from dietary input, they can be synthesized by de
novo lipogenesis, elongation and desaturation (15).
There are various methods used to evaluate dietary intake
of fatty acid in nutritional epidemiology. Dietary assessment
methods have several limitations that may weaken both the
accuracy and precision of the measurement, such as un-
derreporting of respondents (16), interviewer bias and lack
of well-matched food composition databases (17). Alternati-
vely, fatty acid biomarkers in blood or tissues could be more
accurate and convenient for estimating long-term dietary
fatty acid intake (17). Previous studies in many populations,
including in patients with CKD (Fig. 1), have suggested that
fatty acid proportions in serum cholesterol esters, phospho-
lipids, as well as adipose tissue are good indicators of the
corresponding habitual intake of fatty acids of exogenous
origin, including EPA and DHA (18-21).
Fat levels In dIets oF cKd patIents
Earlier studies investigating whether CKD patients eat a diet
with a healthy fat profile indicate that the dietary contents
of n-6 PUFA and EPA are often decreased in hemodialysis
(HD) patients (22, 23). Friedman et al (24) later reported that
American HD patients consume fish, a major source of EPA
TABLE I
MAJOR DIETARY SOURCES OF FATTY ACIDS
Common name Chemical structure* Dietary sources
Saturated fatty acids
Palmitic acid 16:0 Meats, cheeses, butter, palm oil
Stearic acid 18:0 Animal fat, cocoa butter and shea butter
Monounsaturated fatty acids
Palmitoleic acid 16:1 n-7 Macadamia oil, sea buckthorn oil
Oleic acid 18:1 n-9 Sunflower oil, safflower oil
Polyunsaturated fatty acids
n-6 subfamily
Linoleic acid 18:2 n-6 Sunflower seed, corn, soya, sesame, canola,
safflower and their oils
Gamma-linolenic acid 18:3 n-6 Evening primrose oil
Dihomo-gamma-linolenic acid 20:3 n-6 Meats, chicken
Arachidonic acid 20:4 n-6 Meat, eggs
n-3 subfamily
Alpha-linolenic acid 18:3 n-3 Rapeseed, soybeans, walnuts, flaxseed,
perilla, chia, hemp and their oils
Eicosapentaenoic acid 20:5 n-3 Oily fish, seafood, seaweed, krill oil, seal oil
Docosapentaenoic acid 22:5 n-3 Seal meat and oils
Docosahexaenoic acid 22:6 n-3 Oily fish, seafood, seaweed, krill oil, seal oil
*Chemical structure presented as C:D n-x, where C is the number of carbon atoms and D is the number of double bonds in
the fatty acid. A double bond is located on the xth carbon–carbon bond, counting from the terminal methyl carbon toward the
carbonyl carbon (7).
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and DHA, in quantities far below American Heart Associa-
tion (AHA) recommendations. Recently, the authors further
showed that, generally, HD patients in the United States had
lower levels of n-3 PUFA than nondialysis patients, with US
HD patients presenting the lowest mean levels overall (25).
Khoueiry et al (26) found that the majority of US HD patients
in general consume too much fat – particularly saturated fat –
in their diets. Similar results have been reported in Europe
(27, 28). On the other hand, An et al (29) observed that
dialysis patients in Korea present higher blood n-6 PUFA
levels, while n-3 PUFA levels are similar to those of healthy
control subjects. Since dietary habits differ considerably
across countries and geographic areas, it is essential to
take into consideration regional differences when interpre-
ting data pertaining to fatty acids.
clInIcal assocIatIons oF Fatty acIds and
dIetary Fat supplementatIon
Dietary fat and renal function
Proteinuria/albuminuria and impaired kidney function are
2 key characteristics of CKD, according to the current Kid-
ney Disease Outcomes Quality Initiative (30). Animal studies
showed that n-3 PUFA supplementation may reduce the
progression of renal disease (31). The potential mechanisms
by which n-3 PUFA putatively protects the kidneys from
damage include suppression of mesangial cell activation
and proliferation (32), antiinflammatory influence (33), anti-
proteinuric effects (34-37), reduction in blood pressure (38),
improvement of endothelial function (39), alterations of cell
membrane fluidity and functionality (40-42), as well as gene-
ral hypolipidemic effects (43, 44).
Observational studies suggest that increased PUFA intake
may be protective against the age-related decline in glo-
merular filtration rate (GFR) in the general population. In a
population-based cohort of 931 older Italians, Lauretani
et al (45) reported a negative relationship of both plasma
n-3 and n-6 PUFA with mean GFR change during the fol-
lowing 3 years. Gopinath et al (46) recently found in 2,600
Australian adults that a diet rich in long-chain n-3 PUFA
and fish correlated with a significantly reduced likelihood of
having CKD (GFR <60 ml/min per 1.73 m2), but the authors
did not observe benefits for n-6 PUFA. On the other hand,
an association of n-3 PUFA with GFR was not observed
by Diaz-Lopez et al (47) among 2,123 Spanish nondiabe-
tic individuals, and, interestingly, subjects in the highest
quartile of n-6 PUFA intake had an increased risk of CKD.
Investigations of SFA and kidney function in humans are elu-
sive. In the Nurses’ Health Study, Lin et al (48) found 1.62
increased odds of GFR decline ≥30% during 12 years, in the
women in the highest quartile, compared with those in the
lowest quartile, of SFA intake. However, the effect of SFA
on kidney function was not confirmed in the Reasons for
Geographic and Racial Differences in Stroke (REGARDS)
study (49). Notably, dietary MUFA intake was not significan-
tly related with GFR in these 2 large observational dietary
studies (48, 49). In these 2 studies, higher SFA or animal
fat intake was associated with the presence of albuminuria
(48, 49). Consistently, an analysis from the Multi-Ethnic Stu-
dy of Atherosclerosis (MESA) also reported a direct asso-
ciation between nondairy animal food intake and the urinary
albumin-to-creatinine ratio (50). Although a number of publi-
cations in population-based cohorts have reported no direct
association between n-3 PUFA and albuminuria (48-52), a
recent study in 1,436 type 1 diabetic patients demonstra-
ted an inverse association between dietary long-chain n-3
PUFA and the degree of albuminuria (53). There is no evi-
dence to our knowledge that dietary MUFA and n-6 PUFA
correlate with albuminuria.
There have been many randomized controlled studies
testing the benefits of n-3 PUFA supplementation on pro-
teinuria/albuminuria and renal function in humans mo-
stly with diabetic nephropathy, IgA nephropathy or lupus
nephritis (51, 54-66), as summarized in Table II. Among
Fig. 1 - Relations between individual fatty acid proportions
in dietary records versus serum cholesterol esters (CE), ex-
pressed as standard coefficients (β) in multivariate regression
models, in all individuals with chronic kidney disease (CKD)
as well as in adequate dietary reporters only (reprinted with
permission from Oxford University Press) (21). An acceptable
range of energy intake is determined for each subject in rela-
tion to the estimated energy expenditure taking the level of
physical activity and basal metabolic rate into consideration,
i.e., producing a 95% CI for energy intake required for weight
maintenance. Subjects with reported energy intake within the
95% CI were regarded as adequate dietary reporters. Multi-
variate regression models were adjusted for body mass index,
smoking status, alcohol intake, physical activity, cardiovascu-
lar disease, diabetes, hypertension, hyperlipidemia, glomeru-
lar filtration rate and urinary albumin excretion rate. 16:0 =
palmitic acid; 18:0 = stearic acid; 18:1 = oleic acid; 18:2 = lin-
oleic acid; 20:4 = arachidonic acid; 18:3 = alpha-linolenic acid;
20:5 = eicosapentaenoic acid; 22:6 = docosahexaenoic acid.
4© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
Huang et al: Dietary fat modification in CKD
them, only a few observed significant effects of redu-
cing proteinuria/albuminuria (62, 63, 65) or retarding the
reduction of GFR (62). Although not reaching statisti-
cal significance, the other interventional studies gene-
rally showed benefits for markers of kidney damage.
Also, nonrandomized clinical trials suggested that n-3
PUFA supplementation might be renoprotective (67-70).
A meta-analysis of these interventional studies concluded
that there is a greater reduction in urine protein excretion
in the intervention group than in the control group (Cohen’s
delta for all trials was −0.19; 95% confidence interval
[95% CI], −0.34 to −0.04; p = 0.01) (71). Moreover, this
pooled analysis showed that the decline in GFR is slo-
wer in those receiving n-3 PUFA supplementation than in
the controls, but this effect does not reach significance
(Cohen’s delta for all trials was 0.11; 95% CI, −0.07 to 0.29;
p = 0.24) (71). Reasons for the inconsistencies of these
trials may include differences in etiology, risk factors for
TABLE II
RANDOMIZED CONTROLLED TRIALS OF n-3 POLYUNSATURATED FATTY ACID SUPPLEMENTATION ON KIDNEY
FUNCTION AND PROTEINURIA/ALBUMINURIA, SORTED IN CHRONOLOGICAL ORDER
Study Participants* Duration Intervention Outcome
Haines et al (54) n = 19, DN 6 weeks Capsules, 2.7 g/day EPA
and 1.9 g/day DHA
No effects on UAE or
urinary NAG
Jensen et al (55) n = 18, DN 2 × 8 weeks
(crossover trial)
Cod-liver oil emulsion, 2 g/day
EPA and 2.6 g/day DHA
No effects on UAE or GFR
Bennett et al (51) n = 17, IgA nephropathy 2 years Capsules, 10 g/day EPA No effect on GFR
Clark et al (56) n = 26, lupus nephritis 2 × 1 year
(crossover trial)
Capsules, 2.7 g/day EPA
and 1.7 g/day DHA
No effects on UAE or GFR
Gentile et al (57) n = 20, chronic
glomerulonephritis
2 × 2 months
(crossover trial)
Capsules, 5 g/day fish oil No effect on proteinuria
Pettersson
et al (58)
n = 15, IgA
nephropathy
6 months Capsules, 3.3 g/day EPA
and 1.8 g/day DHA
↓ GFR
No effect on UAE
Rossing et al (59) n = 18, DN 1 year Oil emulsion, 2.0 g/day EPA
and 2.6 g/day DHA
No effects on UAE or GFR
Lungershausen
et al (60)
n = 16, DN 12 weeks Capsules, 2 g/day EPA and
1.4 g/day DHA
No effects on UAE or GFR
Cappelli et al (61) n = 10, chronic renal
failure
12 months Capsules, 3.4 g/day
n-3 PUFA
No effects on UAE or GFR
Alexopoulos
et al (62)
n = 14, IgA
nephropathy
4 years Capsules, 0.85 g/day EPA
and 0.58 g/day DHA
↓ UAE
↑ GFR
Svensson
et al (63)
n = 28, CKD with plas-
ma creatinine between
150 and 400 µmol/L
2 months Capsules, 2.4 g/day
n-3 PUFA
↓ UAE
No effect on GFR
Theobald et al (64) n = 38, healthy
individuals
2 × 3 months
(crossover trial)
Capsules, 0.7 g/day DHA No effect on UAE
Ferraro et al (65) n = 15, IgA
nephropathy
6 months Capsules, 3 g/day n-3 PUFA ↓ Proteinuria
No effect on GFR
Miller et al (66) n = 29, DN 2 × 6 weeks
(crossover trial)
Capsules, 4 g/day n-3 PUFA ↓ Urine NGAL excretion
No effects on UAE or GFR
CKD = chronic kidney disease; DHA = docosahexaenoic acid; DN = diabetic nephropathy; EPA = eicosapentaenoic acid;
GFR = glomerular filtration rate; NAG = N-acetyl-B-glucosaminidase; NGAL = neutrophil gelatinase-associated lipocalin;
PUFA = polyunsaturated fatty acids; UAE = urinary albumin excretion.
*Intervention group.
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disease progression, outcome evaluations, sample sizes,
doses and durations of PUFA administered, compliance of
participants and use of medications.
Blood lipoproteins
CKD is commonly associated with an atherogenic lipoprotein
profile, even when renal function is only mildly compromi-
sed (72). Typically, CKD patients present higher low-density
lipoprotein cholesterol (LDL-C) and apolipoprotein B levels,
and markedly increased triglyceride and lipoprotein(a) levels;
whereas the high-density lipoprotein cholesterol (HDL-C) and
apolipoprotein A1 levels are usually low (73). In the general
population, it has been established that fatty acids influence
the lipid profile. In particular, n-6 PUFAs (especially LA) lower,
but SFA increases, serum cholesterol concentration. Moreo-
ver, n-3 PUFAs reduce serum triglyceride concentration (74).
A number of randomized controlled trials have assessed the
effects of n-3 PUFA supplementation on blood lipoproteins
in CKD (63, 75-87), as summarized in Table III. In the me-
ta-analysis by Pei et al (88), pooled analysis revealed that
n-3 PUFA supplementation significantly reduces plasma tri-
glycerides. Consumption of n-3 PUFA also elevates HDL-
C and total cholesterol as well as reduces LDL-C, without
TABLE III
RANDOMIZED CONTROLLED TRIALS OF n-3 POLYUNSATURATED FATTY ACID SUPPLEMENTATION ON BLOOD
LIPOPROTEINS IN CKD PATIENTS, SORTED IN CHRONOLOGICAL ORDER
Study Patients* Duration Intervention Outcome
Diskin et al (75) n = 3, HD 6 months Capsules, 3 g EPA/HD
session (3 times per week)
No effect on cholesterol
Donnelly et al (76) n = 18
(8 HD, 8 PD)
2 × 4 weeks
(crossover trial)
Capsules, 3.6 g/day
n-3 PUFA
No effects on TG, and total
and HDL cholesterol
Ando et al (77) n = 19
(11 HD, 8 PD)
3 months Capsules, 1.8 g/day EPA ↓ Remnant plasma lipoproteins
↓ Oxidized LDL cholesterol
↓ Total cholesterol
↓ TG
Khajehdehi (78) n = 15, HD 2 months Capsules, 1.5 g/day n-3 PUFA ↑ HDL cholesterol
Schmitz et al (79) n = 12, HD 12 months Capsules, 4 g/day n-3 PUFA ↓ TG
Svensson et al (63) n = 28, CKD with
plasma creatinine
between 150 and
400 µmol/L
8 weeks Capsules, 2.4 g/day n-3 PUFA ↓ TG
↑ HDL cholesterol
Saifullah et al (80) n = 9, HD 3 months Capsules, 1.3 g/day n-3 PUFA ↓ TG (p = 0.08)
Taziki et al (81) n = 10, HD 12 weeks Capsules, 1.2 g/day n-3 PUFA ↓ TG
↑ HDL cholesterol
Svensson et al (82) n = 103, HD 3 months Capsules, 1.7 g/day n-3 PUFA ↓ TG
Bowden et al (83) n = 18, HD 6 months Soft-gel pills, 0.96 g/day EPA
and 0.6 g/day DHA
No effects on lipoproteins
Bowden et al (84) n = 44, HD 6 months Capsules, 0.96 g/day EPA and
0.6 g/day DHA
↑ HDL cholesterol
↓ LDL particle number
Beavers et al (85) n = 18, HD 6 months Capsules, 0.96 g/day EPA and
0.6 g/day DHA
No effect on lipoprotein(a)
Poulia et al (86) n = 25, HD 2 × 4 weeks
(crossover trial)
Capsules, 0.92 g/day EPA and
0.76 g/day DHA
No effects on TG and total
cholesterol
Kooshki et al (87) n = 17, HD 10 weeks Capsules, 2 g/day n-3 PUFA ↓ TG
CKD = chronic kidney disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; HD = hemodialysis; HDL = high-
density lipoprotein; LDL = low-density lipoprotein; PD = peritoneal dialysis; PUFA = polyunsaturated fatty acids; TG = triglyceride.
*Intervention group.
6© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
Huang et al: Dietary fat modification in CKD
reaching statistical significance. The improvements in tri-
glyceride and LDL-C values by n-3 PUFA may be a conse-
quence of reduced hepatic synthesis (89).
Nutritional status
Insufficient dietary energy intake is common among CKD
patients, and is considered a major cause of malnutrition
in this population (90, 91). Fatty acids are important and
efficient sources of energy in humans. There have been
some interventional studies exploring the beneficial effect of
n-3 PUFA on nutritional status in HD subjects, such as dry
weight gain and improved serum albumin. Although some
studies showed encouraging results (92, 93), others did not
observe a significant impact on nutritional status (94-96). It
has been suggested that n-3 PUFA supplementation may
improve nutritional status via reduction in inflammation and
catabolism (92, 93). Studies in this area have been characte-
rized, however, by their small sample size and short-term
follow-up, which limit the possibility of making any strong
statement on this issue.
Inflammation
The inflammatory process is modulated by various media-
tors, including compounds generated from fatty acid pre-
cursors. The n-3 PUFAs have been investigated in vitro,
in vivo and in clinical studies and are considered to exert
pleiotropic antiinflammatory properties in several diseases
(97). Eicosanoids are proinflammatory signaling molecules
derived from either n-6 or n-3 PUFA. The eicosanoids de-
rived from n-3 PUFA are less proinflammatory than those
derived from n-6 (98, 99). The amounts and balance of these
PUFAs therefore affect the inflammatory process. Additional
antiinflammatory effects of n-3 PUFAs include attenuation
of endothelial adhesiveness, activation of leukocytes and
resident macrophages, leukocyte–endothelial interaction,
leukocyte transmigration and the release of substances that
lead to tissue injury (97).
Given the evidence relating CKD to persistent low-grade in-
flammation (90, 100), some observational studies have inve-
stigated the link between PUFAs and inflammation in CKD
patients. However, the literature does not show a consistent
association between n-3 PUFA and inflammation in dialysis
subjects (101, 102). It has been reported that dialysis pa-
tients consume insufficient n-3 PUFA and consequently
have low blood levels (25, 80, 103). The reduced circula-
ting levels may not suffice to exert their antiinflammatory ef-
fects. Data on n-6 PUFAs are so far rare. Recently, we found
that circulating LA correlates with reduced interleukin-6
concentrations in Swedish dialysis patients (Fig. 2) (102),
in agreement with population-based studies (104-107). In-
creasing evidence supports a net antiinflammatory effect of
LA in humans (13). LA suppresses the production of adhe-
sion molecules, chemokines and interleukins in vitro (108).
Arachidonic acid, one of the LA metabolites, is also favora-
bly linked with circulating proinflammatory and antiinflam-
matory markers in humans (107). For this reason, the AHA
recommendations suggest an n-6 PUFA intake of at least
5%-10% of total energy, for prevention of CVD (13). SFAs
can directly cause inflammation; they increase the expres-
sion and secretion of inflammatory cytokines (109-111) and
induce nuclear factor-kappa B activation (112). Stearoyl-
CoA desaturase-1 (SCD-1) converts dietary saturated fatty
acids into monounsaturated fatty acids and is regulated by
feedback inhibition. Thus, elevated SCD-1 activity signifies
excess SFA intake. In dialysis patients, we observed that
estimated SCD-1 activities both in liver and adipose tissue
were positively linked with inflammation, as shown in Figure
3 (113). It remains, however, to be shown in humans whe-
ther SCD-1 per se has adverse health effects. On the other
hand, there is convincing evidence that replacing dietary
SFA by n-6 PUFA reduces cardiovascular events in obese
subjects (114). In this context, a randomized clinical trial
replacing SFA with PUFA while maintaining adequate pro-
tein and energy intake would be a feasible means for testing
the putative roles of SCD-1 in CKD patients (115).
Fig. 2 - Spearman’s rank correlation between linoleic acid and
serum interleukin-6 concentrations in 222 dialysis patients
(reprinted with permission from Oxford University Press) (102).
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Much interest has been given to the antiinflammatory be-
nefits of n-3 PUFA supplementation in the potential mana-
gement of patients with CKD (23, 80, 83, 92, 96, 116-120),
as shown in Table IV. In general, clinical trials show that
supplementation with n-3 PUFA has the potential to redu-
ce inflammatory markers in CKD patients – e.g., C-reactive
protein (80, 83, 92, 118, 119, 121, 122), interleukin-6 (120-
123), tumor necrosis factor-α (121-124) and soluble inter-
cellular adhesion molecule type 1 (125). These findings in
turn support the speculation from observational research
that reduced circulating n-3 PUFA in dialysis patients has
an effect on few antiinflammatory properties. Data on ef-
fects of n-6 PUFA supplementation in CKD patients are
almost nonexistent, with only 1 study demonstrating a
trend toward reduction in leukotriene B4 (a proinflammatory
eicosanoid) production (117). Thus, more research focus
should be given to the potential antiinflammatory effect of
n-6 PUFA.
Thrombosis and vascular access patency
Maintaining a long-term functioning arteriovenous access is
a major clinical challenge in management of HD patients.
Due to the antithrombotic, antiproliferative and platelet an-
tiaggregatory effects (126), supplementation with n-3 PUFA
has been proposed as an approach to improve access
patency in HD patients (127, 128). Schmitz et al (79) in a
double-blind randomized trial of 24 HD patients demonstra-
ted a 60% higher graft patency rate in the first year of HD
treatment in those with an intake of 2.7 g/day of fish oil,
compared with the control group. Lok et al (129) recently
conducted a cornerstone study on this issue (the Fish Oil
Inhibition of Stenosis in Hemodialysis Grafts study; FISH
study). In this randomized, double-blind, controlled clinical
trial, 201 uremic patients with new HD grafts received fish
oil capsules (4 g/day) for 12 months. The primary outcome
was the proportion of grafts with loss of native patency, for
which the intervention observed a close to significant effect
of fish oil supplementation as compared with the control
group (48% vs. 62%, respectively; relative risk 0.78; 95%
CI, 0.60-1.03; p = 0.06). The secondary outcome was the
rate at which this loss of native patency occurred. In this
case, fish oil was associated with improved graft patency,
lower rates of thrombosis and of failures. This striking fin-
ding does not agree with an earlier report (130). Currently,
there is 1 large ongoing randomized trial designed to test
whether fish oils have any theoretical potential for preven-
ting these outcomes (131).
Dietary fat, cardiovascular events and survival
Results from observational studies addressing the associa-
tion between dietary fat and outcomes in CKD patients are
elusive (127, 128, 132). In a prospective cohort study, Kutner
et al (133) found that the consumption of fish in dialysis pa-
tients was associated with an approximately 50% lower rate
of mortality over 3 years. Also, Hamazaki et al (134) show-
ed that Japanese dialysis patients in the highest tertile of
erythrocyte DHA content had a reduced mortality risk. In
a recent nested case-control study, Friedman et al (135)
observed a strong and independent association between
higher n-3 PUFA levels and a lower risk of sudden cardiac
death throughout the first year of dialysis in incident HD pa-
tients. However, another study in 93 prevalent HD patients
did not find a significant association between erythrocyte
n-3 PUFA proportions and mortality (136). Adding to this
controversy, we could not observe any association between
plasma phospholipid n-3 PUFA proportions and mortality in
Swedish dialysis patients (102). This negative result is in line
with results from a study using dietary n-3 PUFA estimations
in US HD patients (101) as well as in Swedish community-
based reports (137). The divergences in results may at least
partly be attributed to the substantially different amount of
fish intake in the study populations (US vs. Japanese vs.
Swedish populations) – namely, the intake of n-3 PUFA in
Fig. 3 - Correlation between stearoyl-CoA desaturase-1
(SCD-1) activity indices in plasma phospholipids (PL) and
serum interleukin-6 concentrations in dialysis patients
(reprinted with permission from John Wiley and Sons) (113).
Spearman’s rho = 0.27, p<0.001.
8© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
Huang et al: Dietary fat modification in CKD
most Western countries and particularly in the United States
is generally insufficient and lower than in Japan. Thus, these
findings should be interpreted within the context of dietary
habits. In addition, methodological issues (food frequency
questionnaires vs. plasma PUFA proportions vs. erythrocyte
n-3 PUFA content) and study design (fatty acids as catego-
rical vs. continuous variables in the studies) may have con-
tributed to the differences in results.
There has been emerging evidence on the association
between n-6 PUFA and mortality in CKD. In an observa-
tional study, we showed that the proportion of LA in pla-
sma phospholipids was inversely associated with all-cause
mortality in dialysis patients (102). This finding agrees with
studies from the general population (13, 137-141). Mecha-
nisms by which LA may be linked to reduced mortality may
include improvement in insulin sensitivity and reduced risk
of developing type 2 diabetes mellitus (142, 143), as well as
lowering of inflammatory markers (108), cholesterol (142)
and blood pressure (144). Further research is needed to
confirm these results.
Dietary modifications toward high PUFA intake have the po-
tential to reduce mortality in populations at high CVD risk.
Two large randomized clinical trials, the GISSI-Prevenzione
(145) and JELIS trials (146), showed that n-3 PUFA supple-
mentation was associated with a significant reduction in
deaths from cardiac causes in non-CKD populations. Yet,
in renal patients, only 1 trial investigated the potential of
n-3 PUFA supplementation to reduce hard end points: 206
HD patients were randomly assigned to treatment with n-3
PUFA (capsules giving 1.7 g/day n-3 PUFA) or placebo (oli-
ve oil) and were followed for 2 years. The primary end point
was a composite of cardiovascular events and death, for
TABLE IV
RANDOMIZED CONTROLLED TRIALS OF n-3 POLYUNSATURATED FATTY ACID SUPPLEMENTATION ON INFLAMMA-
TION IN CKD PATIENTS, SORTED IN CHRONOLOGICAL ORDER
Study Patients* Duration Intervention Outcome
Peck et al (23) n = 8, HD 8 weeks Capsules, 6 g/day fish oil ↑ PGE2 (0.10 > p>0.05)
Løssl et al (116) n = 8, HD 12 weeks Capsules, 5.2 g/day n-3 PUFA ↓ LTB4
↑ LTB5
Begum et al (117) n = 12, HD 16 weeks Capsules, 4.4 g/day n-3 PUFA ↓ LT B 4
Saifullah et al (80) n = 15, HD 3 months Capsules, 1.3 g/day n-3 PUFA ↓ CRP
Madsen et al (118) n = 22, CKD
stages 3-4
8 weeks Capsules, 2.4 g/day n-3 PUFA ↓ CRP (p = 0.06)
Moreira et al (119) n = 31, HD with
CRP <50 mg/L
8 weeks A canned sardine sandwich/HD
session (3 times per week)
↓ CRP only in sensitivity
analyses
Himmelfarb
et al (120)
n = 31, HD 8 weeks Capsules, 0.8 g/day DHA ↓ IL-6, WBC, neutrophil
fraction of WBC
Ewers et al (92) n = 40, HD 2 × 6 weeks
(crossover trial)
Capsules, 3 g/day n-3 PUFA ↓ CRP
Bowden et al (83) n = 18, HD 6 months Soft-gel pills, 0.96 g/day EPA
and 0.6 g/day DHA
↓ CRP
Kooshki et al (125) n = 17, HD 10 weeks Capsules, 1.24 g/day EPA and
0.84 g/day DHA
↓ sICAM-1
Daud et al (96) n = 32, HD with se-
rum albumin <39 g/L
6 months Capsules, 1.8 g EPA and 0.6 g
DHA/HD session (3 times per week)
No effect on CRP
CKD = chronic kidney disease; CRP = C-reactive protein; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; HD = he-
modialysis; IL = interleukin; LTB = leukotriene B; PGE = prostaglandin E; PUFA = polyunsaturated fatty acids; sICAM-1 = soluble
intercellular adhesion molecule type 1; WBC = white blood cells.
*Intervention group.
9
© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
JN (0000; :00) 000- 00000
EPHROL
which intervention groups did not differ (hazard ratio 1.04;
95% CI, 0.72-1.48, p = 0.80). The secondary end points
were incidence of myocardial infarction and major corona-
ry events, where the n-3 PUFA supplemented group sho-
wed significantly lower incidence rates than the placebo
group (147).
Other effects
Due to its diverse physiological effects, PUFAs have been
studied with regard to a number of other risk factors relevant
to advanced CKD (127, 128). Previous reports showed that
PUFAs may also have favorable effects on plasma homocy-
steine levels (148), vascular calcification (149), adipokines
(150), blood pressure (129, 151), antioxidation (81, 122,
152), lipoxygenase activity (117), pruritus (23, 117, 128, 153,
154), atrial fibrillation (155), reduction in erythropoietin requi-
rements (128), metabolic syndrome and insulin resistance
(Huang et al, Serum fatty acid patterns, insulin sensitivity
and the metabolic syndrome in individuals with chronic kid-
ney disease submitted).
Summary
Evidence from several lines of research supports the hypo-
thesis that n-3 PUFAs might have therapeutic potential in
reducing proteinuria in CKD and reducing triglycerides and
inflammation in dialysis patients. On the other hand, the
evidence remains weak due to inappropriate design, small
sample size and short duration of most of the studies. At
present, fish oil supplementation should not be administe-
red with these intentions exclusively. Rather, increased in-
take of oily fish should be advocated for cardioprotection
(AHA recommendations). As in the general population,
emerging evidence in CKD suggests that LA is beneficial
for a number of CVD risk factors, such as inflammation and
LDL-C. More studies are needed in CKD patients in this re-
gard. Consumption of oily fish in the context of plant-based
diets, such as in the Mediterranean diet, which is rich in LA
and other healthy nutrients and has less SFA, is likely to be
of particular benefit to patients who have CKD, or are at risk
of developing CKD.
Financial support: We received research grants from the Swedish
Research Council, the Swedish Kidney Foundation, the Marianne
and Marcus Wallenberg, and the Osterman’s, Westman’s and Thu-
ring’s Swedish foundations, as well as the Strategic Research Pro-
gram in Diabetes at Karolinska Institutet.
Conflict of interest: Baxter Novum is the result of a grant from
Baxter Healthcare Corporation to the Karolinska Institutet. B.L. is
employed by Baxter Healthcare Corporation. None of the other
authors declared any conflict of interest.
Address for correspondence:
Xiaoyan Huang
Karolinska Institutet
Divisions of Renal Medicine and Baxter Novum
Karolinska University Hospital at Huddinge K56
Karolinska Institutet
SE-14186 Stockholm
Sweden
xiaoyan.huang@ki.se
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Accepted: March 26, 2013
