Original Investigation

Effects of Mediterranean Diets on Kidney Function: A Report

From the PREDIMED Trial
Andrés Díaz-López, RD,1,2 Mònica Bulló, BSc, PhD,1,2 Miguel Ángel Martínez-González, MD, PhD,2,3
Marta Guasch-Ferré, RD,1,2 Emilio Ros, MD, PhD,2,4 Josep Basora, MD,1,2 María-Isabel Covas,
DPharm, PhD,2,5 Maria del Carmen López-Sabater, DPharm, PhD,6 and Jordi Salas-Salvadó, MD,
PhD,1,2 on behalf of the PREDIMED (Prevención con Dieta Mediterránea) Reus Study Investigators

Background: Epidemiologic observations have linked healthy dietary patterns to improved kidney function.
Study Design: We assessed the effects of the Mediterranean diet (MedDiet) on kidney function in both a
cross-sectional assessment and after a 1-year intervention in a cohort of the PREDIMED (Prevención con
Dieta Mediterránea) Study, a multicenter 3-arm randomized clinical trial to determine the efficacy of the
MedDiet on primary cardiovascular prevention.
Setting & Participants: Community-dwelling men aged 55-80 years and women aged 60-80 years at
high risk of cardiovascular disease from Reus, Spain.
Intervention: Participants were randomly assigned to 3 ad libitum diets: a MedDiet supplemented with virgin
olive oil (MedDiet olive oil), a MedDiet supplemented with mixed nuts (MedDiet nuts), or a control low-fat diet.
Outcomes: Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (ACR).
Measurements: Nutrient intake, adherence to the MedDiet, lifestyle variables, cardiovascular risk factors,
serum urea and creatinine concentrations, eGFR, and urinary ACR were evaluated at baseline and after
intervention for 1 year.
Results: Baseline kidney function markers were similar across quartiles of adherence to the MedDiet in
785 participants (55% women; mean age, 67 years). After a 1-year intervention in 665 participants, the 3
dietary approaches were associated with improved kidney function, with similar average increases in eGFR
(4.7 [95% CI, 3.2-6.2], 3.5 [95% CI, 1.9-5.0], and 4.1 [95% CI, 2.8-5.5] mL/min/1.73 m2 for the MedDiet olive
oil, MedDiet nuts, and control groups, respectively [P 0.001 vs baseline for each; P 0.9 for differences
among groups]), but no changes in ACRs after adjustment for various confounders.
Limitations: Generalization of results to other age groups or ethnicities. GFR was not directly measured.
Conclusions: The results do not support the notion that the MedDiet has a beneficial effect on kidney
function over and above that of advice for a low-fat diet in elderly individuals at high cardiovascular risk.
Am J Kidney Dis. 60(3):380-389. © 2012 by the National Kidney Foundation, Inc.

INDEX WORDS: Mediterranean diet; kidney function; creatinine; glomerular filtration rate; albuminuria;
PREDIMED (Prevención con Dieta Mediterránea) Study.

hronic kidney disease (CKD) is a worldwide
C public health problem due to an increase in both
incidence and prevalence in the last decades. 1-3 The NKF-
KDOQI (National Kidney Foundation’s Kidney Disease
Outcomes Quality Initiative) defined CKD as kidney dam-
age usually signaled by the presence of albuminuria and/or
decreased kidney function. 4,5 A low estimated glomerular
filtration rate (eGFR) and albuminuria are independent
predictors of major cardiovascular events and mortality. 6,7
Moreover, current evidence suggests that traditional cardio-
vascular risk factors, such as advanced age, 8 hyperten-
sion,9,10 type 2 diabetes,11 obesity,12 and increased circulat-
ing levels of peripheral inflammatory markers,13 are
associated with progression of kidney disease.
Of the lifestyle factors, diet appears to have an
important role in the prevention and development of

From the 1Human Nutrition Unit, Faculty of Medicine and Health
Sciences, IISPV, Universitat Rovira i Virgili, Reus, Tarra-gona;
2
CIBERobn Physiopathology of Obesity and Nutrition, Institute of
Health Carlos III, Madrid; 3Department of Preventive Medicine and
Public Health, University of Navarra, Pamplona; 4Lipid Clinic,
Service of Endocrinology and Nutrition, Institut d’Investigacions
Biomèdiques August Pi Sunyer, Hospital Clínic; 5Cardiovascular
Risk and Nutrition Research Group. IMIM- Insti-tut de Recerca
Hospital del Mar; and 6Department of Nutrition and Bromatology,
School of Pharmacy, Barcelona, Spain.
Received October 23, 2011. Accepted in revised form February
17, 2012. Originally published online April 30, 2012.
*A list of the PREDIMED Study Investigators appears in the
Acknowledgements.
Trial registration: www.controlled-trials.com; study number:
ISRCTN35739639.
Address correspondence to Jordi Salas-Salvadó, MD, PhD (E-
mail: jordi.salas@urv.cat ), or Mònica Bulló, BsC, PhD (E-mail:
monica.bullo@urv.cat), Human Nutrition Unit, Faculty of
Medicine and Healthy Sciences, Universitat Rovira i Virgili,
C/Sant Llorenç 21, 43201 Reus, Spain.
© 2012 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2012.02.334

380 Am J Kidney Dis. 2012;60(3):380-389

Mediterranean Diet and Kidney Function
CKD.14 The potential effect of diet on kidney
function is attributable in part to its ability to
modulate cardio-vascular risk factors involved in the
development and persistence of decreased kidney
function. Some nutri-tional factors or dietary patterns
have been implicated in the progression of kidney
disease.15-19 However, no specific dietary pattern
able to prevent or ameliorate CKD has been
recognized by high-level evidence-based studies.
Three cross-sectional studies18,20,21 and 1 prospec-
tive investigation22 have examined the association
between dietary patterns and risk of microalbuminuria
or decrease in kidney function. All these epidemio-logic
studies, conducted in apparently healthy young or
middle-aged individuals from different popula-tions,
showed that greater adherence to healthy di-etary
patterns, including the Mediterranean diet (Med-Diet),
was associated inversely with microalbuminuria or
decreasing kidney function.
Because results of epidemiologic studies cannot
firmly establish causal relationships, intervention stud-
ies may help provide a greater degree of scientific
evidence for whether a given dietary pattern is associ-
ated with changes in kidney function. The aim of the
present study was to examine, in the framework of the
PREDIMED (Prevención con Dieta Mediterránea) trial,
whether the traditional Mediterranean dietary pattern
was able to improve kidney function in com-parison to
a control low-fat diet in an elderly popula-tion with
multiple cardiovascular risk factors.
METHODS
Study Design and Population
In the present study, we conduct both a cross-sectional and a
longitudinal assessment of participants from the Reus-Tarragona
area (Spain) who had undergone at least 1 year of follow-up in
the PREDIMED trial at the time of analysis. The PREDIMED
Study is a large, parallel-group, randomized, multicenter,
controlled, 4-year clinical trial aimed to assess the effect of the
MedDiet on the primary prevention of cardiovascular disease
(www.predimed.org; www.predimed.es). The design of the
PREDIMED trial has been reported in detail elsewhere.23
Eligible participants were community-dwelling men aged 55-80
years and women aged 60-80 years who were free of cardiovascu-lar
disease at baseline and fulfilled at least one of the following 2 criteria:
type 2 diabetes mellitus and/or the presence of 3 or more coronary
heart disease risk factors: Family history of early-onset coronary heart
disease (before age 55 years in men or before age 65 years in women)
in first-degree relatives, current smoking, obesity or overweight (body
mass index $25 kg/m2), hypertension (blood pressure 140/90 mm Hg
or treatment with antihyperten-sive medication), or dyslipidemia,
with at least one of the follow-ing: hypercholesterolemia (low-density
lipoprotein cholesterol $160 mg/dL), low plasma high-density
lipoprotein cholesterol level (#40 mg/dL in men or #50 mg/dL in
women), or treatment with lipid-modulating agents. Exclusion criteria
included history of cardiovascular disease, any severe chronic illness,
alcohol or drug addiction, history of food allergy or intolerance to
olive oil or
Am J Kidney Dis. 2012;60(3):380-389
nuts, or low predicted likelihood of changing dietary habits
accord-ing to the stages-of-change model.24
All participants provided informed consent to a protocol ap-
proved by the ethical committees of Clinical Investigation of the
Sant Joan University Hospital (Reus, Spain) and the Jordi Gol i
Gurina Foundation.
Randomization and Intervention
Eligible candidates were invited to attend a screening visit that
included a face-to-face interview with an investigator and
adminis-tration of a 26-item questionnaire to inquire about
medical condi-tions and risk factors related to eligibility. After the
screening visit, participants were randomly assigned by means of
a computer-generated random-number sequence to 1 of the 3
PREDIMED dietary interventions: a MedDiet supplemented with
virgin olive oil (MedDiet olive oil), a MedDiet supplemented with
mixed nuts (MedDiet nuts), or a control low-fat diet.
A behavioral intervention promoting the MedDiet was imple-
mented in both MedDiet groups, as described.23 In brief, on the
basis of the initial assessment of individual scores of adherence
using a 14-item questionnaire,25 dietitians gave personalized di-
etary advice to participants randomly assigned to both MedDiet
groups, with instructions directed to scale up the score, including,
among others (1) abundant use of olive oil for cooking and
dressing; (2) increased consumption of fruit, vegetables, legumes,
and fish; (3) reduction in total meat consumption, recommending
white meat instead of red or processed meat; (4) preparation of
homemade sauce with tomato, garlic, onion, and spices with olive
oil to dress vegetables, pasta, rice, and other dishes; (5) avoidance
of butter, cream, fast food, sweets, pastries, and sugar-sweetened
beverages; and (6) for alcohol drinkers, moderate consumption of
red wine.
At baseline and every 3 months, dietitians administered both
individual interviews and group sessions with a maximum of 20
participants, separately for each group. Sessions consisted of
informative talks and delivery of written material with detailed
descriptions of typical foods for each dietary pattern, seasonal
shopping lists, meal plans, and recipes. Participants assigned to
MedDiet groups were given free allotments of either virgin olive
oil (15 L every 3 months) or mixed nuts (30 g/d; 15 g/d of
walnuts, 7.5 g/d of almonds, and 7.5 g/d of hazelnuts).
Participants ran-domly assigned to the control diet received
recommendations to reduce all types of fat intake, from both
animal and vegetable sources, as recommended by the American
Heart Association guidelines.26 To encourage adherence, small
nonfood gifts, such as kitchenware, tableware, aprons, or
shopping bags, were given. Energy restriction was not advised
and physical activity was not promoted.
Measurements
At baseline and after 1 year of follow-up, we administered: (1) a
47-item questionnaire about education, lifestyle, history of ill-nesses,
and medication use; (2) a validated semiquantitative 137-item food
frequency questionnaire27 to determine energy and nutrient intake
using Spanish food composition tables28; (3) a validated Spanish
version of the Minnesota Leisure Time Physical Activity
Questionnaire29 to evaluate physical activity; and (4) a 14-point
Mediterranean Diet Adherence Screener (MEDAS) to assess the
degree of adherence to the MedDiet (values of 0 or 1 were assigned to
each of 14 items; minimum score 0, maximum score 14). 25 In
addition, anthropometric variables and blood pressure were measured.
Waist circumference was measured mid-way between the lowest rib
and the iliac crest. Blood pressure was measured in triplicate using a
validated semiautomatic oscillom-eter with a 5-minute interval
between each measurement (Omron
381

HEM-705CP; www.omron-healthcare.com/en/index.html),
follow-ing the procedures recommended by the European
Hypertension Society.30 All measurements were performed by
trained profession-als.
At baseline and after intervention for 1 year, blood and urine
samples were obtained after an overnight fast. Aliquots of serum,
EDTA plasma, and urine were immediately prepared, coded, and
sent to a central laboratory and frozen at 80°C until analysis.
Serum glucose, cholesterol, and triglycerides were measured
using standard enzymatic automated methods. High-density
lipoprotein cholesterol was measured by a precipitation technique.
In a ran-dom sample of PREDIMED participants, we measured
urinary tyrosol and hydroxytyrosol (n 600) by gas
chromatography– mass spectrometry as markers of adherence to
olive oil intake recommendations,31 and the proportion of plasma
a-linolenic acid (n 571), by gas chromatography as a measure of
adherence to nut (walnut) intake guidance.32
Assessment of Kidney Function
Serum urea and creatinine concentrations were determined by
enzymatic reaction with urease and by the modified Jaffé colorimet-
ric method, respectively. Urinary creatinine and albumin concentra-
tions were measured using the modified Jaffé colorimetric method
and the bromcresol green albumin method, respectively. Total
coefficients of variation were 3.5% for serum urea, 4.0% for serum
creatinine, 3.0% for urinary creatinine, and 10.0% for urinary
albumin. All analyses were performed using a Roche Hitachi Modular
DDP clinical analyzer system (Roche Diagnos-tics,
www.roche.es/portal/roche-spain/diagnostics). Urinary albu-min-
creatinine ratio (ACR; albumin was measured in milligrams per liter,
and creatinine, in milligrams per deciliter) was calculated and
reported in milligrams per gram. Microalbuminuria was de-fined as
ACR of 30-300 mg/g, and macroalbuminuria, ACR 300 mg/g
regardless of sex. Based on serum creatinine measurements, GFR was
estimated (eGFR) by the CKD-EPI (CKD Epidemiology
Collaboration) equation for whites33 as a measure of kidney function,
as described next. For women, for serum creatinine level
0.7 mg/dL ( 62 mmol/L), eGFR (mL/min/1.73 m2) 144 (serum
creatinine in mg/dL/0.7) 0.329 (0.993age); for serum
creatinine level 0.7 mg/dL ( 62 mmol/L), eGFR (mL/min/1.73
m2) 144 (serum creatinine in mg/dL/0.7) 1.209 (0.993age).
For men, for serum creatinine level 0.9 mg/dL ( 80 mmol/L),
eGFR (mL/min/1.73 m2) 141 (serum creatinine in mg/dL/ 0.9)
0.411
(0.993age); for serum creatinine level 0.9 mg/dL
( 80 mmol/L), eGFR (mL/min/1.73 m2) 141 (serum creatinine in
mg/dL/0.9) 1.209 (0.993age).
Statistical Analyses
Categorical variables are presented as percentages. Descriptive data
for quantitative variables are presented as mean standard deviation or
mean and 95% confidence interval or median (25th-75th percentiles).
Data were tested first for normal distribution using the Kolmogorov-
Smirnov test. Because values for kidney function markers were
skewed, values were log-transformed be-fore analysis. Baseline
differences among the 3 interventional groups were tested by x2 test
for categorical variables or analysis of variance for continuous
variables. P value for comparison of geometric mean values between
markers of kidney function and degree of adherence to the MedDiet
(categorized into quartiles) by group and between groups of
intervention were determined by using analysis of covariance adjusted
for potential confounders. Bonferroni post hoc test was used to correct
for multiple comparisons. Within-group changes between baseline
and 1-year measurements were analyzed using paired t tests. Changes
between intervention groups were assessed using analysis of
covariance with adjustment for
382
Díaz-López et al
potential confounders. All statistical tests were 2 tailed and the
significance level was set at P # 0.05. Analyses were performed
using SPSS software, version 17.0 (SPSS Inc,
www01.ibm.com/software/ analytics/spss).
RESULTS
Of 1,125 eligible participants, 870 fulfilled inclu-
sion criteria and entered the trial. Lack of baseline
biochemical data limited the cross-sectional analysis
to 785 participants (55% women; mean age, 67
years). For the longitudinal analysis, 665 participants
(56% women; mean age, 67 years) were available
after losses to follow-up and exclusion of those
lacking biochemical data (Fig 1). Clinical
characteristics of 120 participants excluded at 1 year
were similar to those of completers.
Baseline characteristics of study participants by
dietary intervention group are listed in Table 1.
Over-all, 93%, 85%, and 54% of participants had
over-weight/obesity, hypertension, or diabetes
mellitus, re-spectively. No differences among the 3
diet groups were observed in relation to age, sex,
weight, body mass index, prevalence of
cardiovascular risk factors, or use of medication
potentially affecting kidney function. Mean blood
urea, serum creatinine, urinary albumin, ACR, and
eGFR values also were similar among groups. As
listed in Table 2, there were no significant baseline
differences overall or by sex in markers of kidney
function by quartiles of adherence to the MedDiet
after adjusting for potential confound-ers.
Energy intake and consumption of selected nutri-ents
and minerals during the intervention in the 665
participants with 1-year data are listed in Table 3. No
significant between-group differences existed in base-
line energy intake or nutrient or mineral consumption.
Significant differences in changes among groups were
observed in relation to total energy as fat, type of fat
(saturated, monounsaturated, and polyunsaturated),
magnesium, and phosphorus. A significant increase in
fat intake occurred in both MedDiet groups, whereas fat
consumption decreased in the control group. The
increased fat intake in the MedDiet groups was due to
increased intake of polyunsaturated and monounsatu-
rated fats, attributable in part to supplementation with
olive oil and nuts in the respective treatment arms.
Participants assigned to both MedDiet groups also
decreased saturated fat intake and increased magne-
sium and phosphorus intake compared with those
allocated to the control group. MEDAS score, which
measures adherence to the MedDiet, increased substan-
tially in the 2 MedDiet groups (1.68 2.09 in the
MedDiet olive oil group and 1.83 2.00 in MedDiet nut
group; both P 0.001), whereas it increased marginally
in the control group (0.65 2.16; P 0.01). Urinary tyrosol
and hydroxytyrosol
Am J Kidney Dis. 2012;60(3):380-389
Mediterranean Diet and Kidney Function

1125 Assessed
for eligibility

255 excluded
82 did not meet inclusion criteria
127 refused to participate
46 other reasons

870 randomized

291 assigned to 289 assigned to 290 assigned

DietMed+VOO DietMed+nuts to control diet

36 excluded for lack 30 excluded for lack 19 excluded for lack

of biochemical data of biochemical data of biochemical data

255 evaluable 259 evaluable 271 evaluable

participants at participants at participants at
baseline baseline baseline

1 acute MI 1 death from other causes 1 stroke

2 lost during the follow-up 31 excluded for lack of 1 cancer death
38 excluded for lack of biochemical data 1 death from other causes
biochemical data 44 excluded for lack of
Figure 1. Flow chart of study partici- biochemical data
pants. Abbreviations: DietMed, 214 evaluable 227 evaluable 224 evaluable
Mediterra-nean diet; MI, myocardial participants participants participants
infarction; VOO, virgin olive oil. at 1 year at 1 year at 1 year

levels increased from baseline in participants
assigned to the MedDiet olive oil group (P 0.05),
whereas those assigned to MedDiet nuts showed a
nonsig-nificant increase in plasma a-linolenic acid
levels (P 0.09). No changes were detected in the
control group in relation to urinary tyrosol and
hydroxyty-rosol levels, whereas a decrease in plasma
a-linolenic acid level was observed in this group.
The diets were well tolerated and no participant
abandoned the study due to adverse effects. Body
weight at 1 year was similar to baseline, without
between-group differences of 0.18 2.57, 0.04 2.83,
and 0.14 3.15 kg for the MedDiet olive oil, MedDiet
nuts, and control diet, respectively (P 0.7 by analysis
of variance). Likewise, there were no significant
changes from baseline or between groups in systolic
blood pressure: 2.16 17.28, 1.19 17.29, and 4.02
17.31 mm Hg, respectively (P 0.2 by analysis of
variance).
Table 4 lists 1-year changes from baseline in kidney
function markers (serum urea nitrogen, serum creati-
nine, ACR, and eGFR) by intervention group, as well as
differences in changes among groups. Significant 1-year
decreases in serum creatinine concentrations and
increases in eGFRs were observed in the 3 inter-vention
groups, whereas urinary ACR increased non-
significantly in participants allocated to the 2 Med-Diet
groups. However, no significant between-group
differences in changes in kidney function were de-
tected. The same analyses conducted separately for
participants with or without diabetes showed similar
results among groups (Table S1, available as online
supplementary material). There were no significant
differences in between-group changes in kidney
func-tion in obese versus nonobese participants (data
not shown). Likewise, no between-group changes
were observed in individuals with or without eGFR
60 mL/min/1.73 m2. However, 1-year increases in
eGFRs were higher in individuals with eGFR 60
mL/min/ 1.73 m2 compared with those with eGFR 60
mL/min/ 1.73 m2 (Table S2).
Sixteen (7.5%), 10 (4.4%), and 13 (5.8%) partici-
pants in the MedDiet olive oil, MedDiet nuts, and
control diet groups, respectively, developed mi-cro-
or macroalbuminuria during follow-up. The num-ber
of individuals with regression of micro- or mac-
roalbuminuria also was similar among groups. The
incidence of individuals progressing to eGFR 60
mL/min/1.73 m2 during follow-up also was similar
among groups (2.3%, 2.6%, and 3.6% in the
MedDiet olive oil, MedDiet nuts, and control diet
groups, respectively). Similarly, there were no
between-group differences in proportions of
individuals with eGFR increases from 60
mL/min/1.73 m2 to normal dur-ing follow-up
(11.2%, 7.5%, and 5.4% in the MedDiet olive oil,
MedDiet nuts, and control diet groups, respectively).
DISCUSSION
To our knowledge, no prior controlled clinical trial
has evaluated the long-term effects of dietary patterns
on kidney function. Our randomized nutritional inter-
vention study assessed the 1-year effects of a Mediter-
ranean dietary pattern compared with advice for a

Am J Kidney Dis. 2012;60(3):380-389 383

 Díaz-López et al

Table 1. Baseline Characteristics of Study Participants

MedDiet Olive Oil MedDiet Nuts Control Diet

(n 255) (n 259) (n 271) Pa

Age (y) 67.4 5.9 67.3 5.7 67.7 6.0 0.6

Men 112 (55) 114 (44) 123 (45) 0.9
Body weight (kg) 76.1 10.6 75.6 10.4 76.3 11.0 0.7
BMI (kg/m2) 29.7 3.1 29.5 3.3 29.8 3.3 0.6
SBP (mm Hg) 149.9 20.1 152.3 19.2 154.9 22.8 0.07
DBP (mm Hg) 84.8 11.5 84.6 9.7 84.4 12.1 0.9
Current smoker 26 (10) 37 (14) 34 (12) 0.8
Physical activity (kcal/d) 263 262 289 278 236 262 0.07
MEDAS scoreb 8.2 1.9 8.4 1.9 8.1 1.7 0.06
Medication
Statin use 114 (45) 107 (41) 105 (39) 0.4
Antihypertensive agent use 193 (76) 198 (76) 194 (72) 0.4
ARB use 53 (21) 45 (17) 37 (14) 0.09
ACEi use 86 (34) 87 (33) 98 (36) 0.8

Overweight/obesityc 243 (95) 240 (93) 249 (92) 0.3

Blood pressure 140/90 mm Hg 214 (84) 225 (87) 228 (84) 0.6
Type 2 diabetes mellitus 141 (55) 133 (51) 149 (55) 0.6
Fasting glucose (mg/dL) 122.4 42.7 115.5 36.5 119.2 37.2 0.1
LDL cholesterol (mg/dL) 127.2 33.6 126.1 32.1 127.4 34.4 0.9
HDL cholesterol (mg/dL) 55.7 13.4 57.1 15.0 54.6 12.7 0.1
Triglycerides (mg/dL) 132.3 66.0 135.0 68.9 142.7 82.7 0.2
Kidney function parameters
SUN (mg/dL) 41.2 [34.8, 48.9] 40.8 [35.8, 46.9] 39.6 [33.4, 47.5] 0.3
SUN 45 mg/dL 85 (35) 80 (33) 80 (31) 0.6
Serum creatinine (mg/dL) 0.9 [0.7, 0.9] 0.8 [0.7, 0.9] 0.8 [0.7, 1.0] 0.09
Serum creatinine 1.3 mg/dL 15 (6) 11 (4) 15 (6) 0.7
Urinary albumin (mg/dL) 0.40 [0.1, 1.0] 0.39 [0.1, 0.8] 0.40 [0.2, 1.0] 0.3
Urinary ACR (mg/g) 4.9 [2.8, 13.6] 4.1 [2.1, 10.5] 5.2 [2.5, 12.5] 0.1
Urinary ACR 30 mg/g 26 (12) 19 (8) 28 (12) 0.4
eGFR (mL/min/1.73 m2) 75.9 [64.1, 89.1] 80.6 [65.4, 91.8] 79.8 [66.7, 91.8] 0.1
eGFR 60 mL/min/1.73 m2 53 (21) 41 (16) 40 (15) 0.2
Note: Data expressed as mean standard deviation, number (percentage), or median [25th, 75th percentile]. Conversion factors for
units: glucose in mg/dL to mmol/L, 0.05551; cholesterol in mg/dL to mmol/L, 0.02586; triglycerides in mg/dL to mmol/L, 0.01129;
SUN in mg/dL to mmol/L, 0.357; serum creatinine in mg/dL to mmol/L, 88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, 0.01667.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ACR, albumin-creatinine ratio; ARB, angiotensin type 2 receptor
blocker; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL, high-density
lipoprotein; LDL, low-density lipoprotein; MedDiet, Mediterranean diet; SBP, systolic blood pressure; SUN, serum urea nitrogen.
aP value for comparisons between groups calculated with x2 tests for categorical variables or 1-way analysis of variance for
continuous variables.
bMEDAS is a 14-item questionnaire to assess adherence to the MedDiet; higher score corresponds to greater adherence.
c
BMI $25 kg/m2.

low-fat diet on kidney function in a large sample of
elderly individuals with multiple cardiovascular risk
factors. Although the 3 dietary interventions were
associated with improved kidney function, as as-
sessed by eGFR, no significant differences were ob-
served in different kidney function variables among
the 3 treatment groups. Changes in nutritional and
other factors that are known to affect kidney function,
namely protein intake,15 body weight,12,34 and blood
pressure,9,10 were similar among groups. Hence, our
results do not support that a high-fat high–unsaturated
fat MedDiet is better than a reduced-fat diet in improv-
ing kidney function, although a limited number of
epidemiologic studies suggest a positive association
between adherence to the MedDiet and kidney func-
tion.20,21
Two cross-sectional studies conducted in appar-
ently healthy Greek populations20,21 have reported
associations between greater adherence to the Med-
Diet and kidney function markers. In the 3L (Leontio
Lyceum Albuminuria) study in 365 healthy Greek
adolescents, individuals with greater adherence to the
MedDiet showed reduced albuminuria.20 In addition,
in 3,042 adults of both sexes, a direct association

384 Am J Kidney Dis. 2012;60(3):380-389

Am J Kidney Dis. 2012;60(3):380-389

Mediterranean Diet and Kidney Function

Table 2. Baseline Kidney Function Markers by Quartiles of Adherence to the Mediterranean Diet

Men (n 349) Women (n 436)

a a b
Q1 (0-6) Q2 (7-8) Q3 (9-10) Q4 (11-14) P Q1 (0-6) Q2 (7-8) Q3 (9-10) Q4 (11-14) P P

No. 109 58 83 99 75 174 83 104

SUN (mg/dL) 39.7 [33.4, 46.5] 42.1 [34.5, 49.9] 43.8 [34.8, 51.4] 40.8 [34.1, 47.9] 0.2c 40.4 [34.5, 48.0] 40.0 [35.9, 47.0] 39.3 [33.1, 46.5] 39.5 [35.2, 45.6] 0.5c 0.3d
SCr (mg/dL) 0.9 [0.8, 1.1] 1.0 [0.9, 1.2] 1.0 [0.8, 1.1] 0.9 [0.8, 1.1] 0.5c 0.8 [0.6, 0.9] 0.8 [0.7, 0.9] 0.8 [0.7, 0.9] 0.8 [0.7, 0.9] 0.6c 0.3d
UACR (mg/g) 5.7 [3.1, 19.8] 5.8 [2.2, 10.5] 5.2 [1.8, 21.5] 4.6 [2.1, 13.7] 0.2c 3.9 [2.3, 9.9] 4.6 [2.2, 10.4] 4.6 [2.5, 9.1] 3.5 [1.7, 7.0] 0.5c 0.5d
eGFR (mL/min/ 79.8 [67.4, 92.7] 74.4 [64.1, 91.8] 79.8 [66.1, 91.8] 83.1 [66.7, 90.9] 0.5e 78.2 [64.1, 91.0] 76.0 [64.1, 89.1] 78.3 [61.5, 91.0] 78.3 [66.7, 90.0] 0.3e 0.1e
1.73 m2)
Note: Quartiles based on a 14-point food-item score (score range for each quartile is provided in parentheses). Results expressed as median [25th, 75th percentile]. Conversion factors for
units: SUN in mg/dL to mmol/L, 0.357; SCr in mg/dL to mmol/L, 88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, 0.01667.
Abbreviations: eGFR, estimated glomerular filtration rate; Q, quartile; SCr, serum creatinine; SUN, serum urea nitrogen; UACR, urinary albumin-creatinine ratio.
aP value for comparisons between quartiles of Mediterranean diet score by analysis of covariance.
bP value for comparisons between quartiles of Mediterranean diet score in the overall population by analysis of covariance.
cAdjusted for age, leisure-time physical activity, weight, systolic blood pressure, type 2 diabetes mellitus (yes/no), and angiotensin-converting enzyme inhibitor, angiotensin receptor
blocker, and statin medication use.
dAdjusted for sex, age, leisure-time physical activity, weight, systolic blood pressure, type 2 diabetes mellitus (yes/no), and angiotensin-converting enzyme inhibitor, angiotensin
receptor blocker, and statin medication use.
eAdjusted for leisure-time physical activity, weight, systolic blood pressure, type 2 diabetes mellitus (yes/no), and angiotensin-converting enzyme inhibitor, angiotensin receptor blocker,
and statin medication use.
385
 Díaz-López et al

Table 3. Baseline Energy, Nutrient, and Mineral Intake and Changes After Intervention for 1 Year

MedDiet Olive Oil MedDiet Nuts Control Diet

(n 214) Pa (n 227) Pa (n 224) Pa Pb

Energy intake
Baseline (kcal/d) 2,276 582 2,305 537 2,295 573
Change (kcal/d) 64 593 0.1 107 629 0.01 20 638 0.7 0.1

Energy from total protein

Baseline (% kcal) 16.5 2.7 16.8 2.4 16.8 2.6
Change (% kcal) 0.3 2.7 0.2 0.3 2.5 0.06 0.4 3.2 0.3 0.9

Energy from total carbs

Baseline (% kcal) 40.4 6.1 39.9 6.2 39.7 6.4
Change (% kcal) 1.1 7.4c,d 0.04 2.1 7.1 0.001 1.8 7.9 0.002 0.001

Fiber intake
Baseline g/1,000 kcal 10.5 2.9 10.5 2.9 9.9 2.7
Change g/1,000 kcal 0.3 3.2 0.2 0.2 3.1 0.4 0.8 3.2 0.001 0.09

Energy from total fat

Baseline (% kcal) 40.8 5.8 40.9 5.9 41.3 6.3
Change (% kcal) 1.1 7.5c,d 0.04 2.6 7.3 0.001 1.5 8.1 0.01 0.001

% of total fat Saturated

fatty acids
Baseline (%) 26.3 4.0 25.9 4.2 26.5 4.8
Change (%) 1.6 4.7 0.001 2.4 4.8e 0.001 0.9 5.5 0.01 0.02
MUFAs
Baseline (%) 49.5 5.1 49.8 4.9 49.6 5.1
Change (%) 2.2 6.4c,d 0.001 0.4 6.0 0.4 1.2 5.9 0.5 0.001
PUFAs
Baseline (%) 15.8 3.9 16.2 3.7 15.4 3.3
Change (%) 0.4 4.3d 0.2 3.4 5.1e 0.001 0.1 4.4 0.8 0.001

Alcohol
Baseline (g/d) 7.1 10.8 8.7 11.9 7.8 13.3
Change (g/d) 0.6 10.4 0.4 0.4 9.7 0.5 0.3 9.2 0.7 0.6

Calcium
Baseline (mg/d) 1,027 325 1,034 363 1,054 394
Change (mg/d) 30 342 0.2 10 368 0.7 49 382 0.08 0.07

Magnesium
Baseline (mg/d) 367 101 374 103 360 92
Change (mg/d) 15 109 0.05 35 121e 0.001 2 102 0.8 0.002

Sodium
Baseline (mg/d) 2,570 909 2,598 925 2,595 954
Change (mg/d) 59 970 0.4 98 1078 0.2 51 998 0.5 0.9

Phosphorus
Baseline (mg/d) 1,715 412 1,726 443 1,709 426
Change (mg/d) 40 444 0.2 89 479e 0.01 56 419 0.06 0.001

Potassium
Baseline (mg/d) 4,197 1169 4,314 1078 4,109 978
Change (mg/d) 182 1,303 0.05 38 1,209 0.6 64 1,178 0.5 0.5
Note: Data expressed as mean standard deviation. P 0.05 indicates statistical significance.
Abbreviations: carbs, carbohydrates; MedDiet, Mediterranean diet; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated
fatty acid.
aP value for differences from baseline by paired t test.
bP value for differences between groups by analysis of covariance adjusted for sex, age, and total energy intake.
c
P 0.05 for differences between MedDiet olive oil and control diet group.
dP 0.05 for differences between MedDiet olive oil and MedDiet nuts group.
e
P 0.05 for differences between MedDiet nuts and control diet group.

386 Am J Kidney Dis. 2012;60(3):380-389

Mediterranean Diet and Kidney Function

Table 4. Changes in Kidney Function From Baseline to 1 Year of Dietary Intervention

MedDiet Olive Oil MedDiet Nuts

(n 214) Pa (n 227) Pa Control Diet (n 224) Pa Pb

SUN (mg/dL) 1.1 ( 0.1 to 2.3) 0.09 0.6 ( 2.1 to 0.8) 0.4 0.2 ( 1.3 to 1.8) 0.7 0.06c
SCr (mg/dL) 0.05 ( 0.07 to 0.03) 0.001 0.05 ( 0.09 to 0.01) 0.03 0.05 ( 0.07 to 0.03) 0.001 0.5c
UACR (mg/g) 2.1 ( 1.2 to 5.4) 0.2 3.1 ( 0.3 to 6.6) 0.08 0.6 ( 5.2 to 4.0) 0.8 0.6c
eGFR (mL/min/ 4.7 (3.2 to 6.2) 0.001 3.5 (1.9 to 5.0) 0.001 4.1 (2.8 to 5.5) 0.001 0.9d
1.73 m2)
Note: Data expressed as mean (95% confidence interval). Conversion factors for units: SUN in mg/dL to mmol/L, 0.357; SCr in
mg/dL to mmol/L, 88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, 0.01667.
Abbreviations: eGFR, estimated glomerular filtration rate; MedDiet, Mediterranean diet; SCr, serum creatinine; SUN, serum urea
nitrogen; UACR, urinary albumin-creatinine ratio.
aP value for differences from baseline by paired t test.
bP value for differences between groups by analysis of covariance.
c
Values were adjusted for sex, age, baseline measure, baseline leisure-time physical activity, and changes in weight, systolic blood pressure,
fasting glucose level, and angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and statin medication use. dValues were
adjusted for baseline measure, baseline value physical activity in leisure time, and changes in weight, systolic blood pressure, fasting
glucose level, and angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and statin medication use.

between adherence to the Mediterranean dietary pat-
tern and creatinine clearance rate also was shown.21
In contrast to these results, in our study, we found no
significant associations between adherence to the
Med-Diet and several variables of kidney function.
That our study group was made up of older
individuals at high cardiovascular risk compared
with healthy young or middle-aged individuals in
prior studies might explain in part the discrepant
findings. More impor-tantly, the cross-sectional
design of the 2 previous studies with the potential for
reverse-causation bias makes them not directly
comparable with our results in a randomized trial.
The association between dietary patterns different
from the MedDiet and renal outcomes recently has been
reported from the large prospective Nurses’ Health
Study (NHS).22 In that study, women in the top quartile
of the DASH (Dietary Approach to Stop Hypertension)
adherence score had a nearly 40% decreased risk of
rapid eGFR decrease compared with those in the
reference quintile during the 11-year follow-up.
However, no association was shown for
microalbuminuria. In contrast, in the same study,
adherence to a Western dietary pattern was associated
with significantly increased odds of microalbuminuria
and rapid kidney function decrease.22 Additionally, in
MESA (Multi-Ethnic Study of Atherosclerosis), a
dietary pattern rich in whole grains, fruit, and low-fat
dairy foods was associated significantly with lower
urinary ACR.18 In contrast to our findings of a lack of
association of kidney function with increasing adher-
ence to the MedDiet, results of the NHS22 and MESA18
support the notion that increasing adherence to a
healthy dietary pattern can improve kidney function and
decrease the risk of renal deterioration. However, they
are consistent with the amelioration of kidney function
observed after 1 year of reinforcing healthy
dietary patterns, either MedDiet or a low-fat diet, in
our clinical trial.
It has been proposed20,21 that the putative associa-
tion between adherence to the MedDiet and improved
kidney function might be explained by the known
effects of this dietary pattern and its components on
several cardiometabolic risk markers, such as im-
proved plasma lipid profiles, blood pressure and insu-
lin sensitivity, and decreased oxidative stress, inflam-
mation, and endothelial dysfunction.35-38 Although the
MedDiets used in the PREDIMED Study have shown
their potential to improve both cardiovascular risk
biomarkers37,39 and cardiometabolic outcomes40,41 in
comparison to the control diet, we could not show that
they were superior to improve kidney function. Because
the decrease in kidney function usually takes many
years,1 the duration of our study (1 year) might not
have been enough to detect a specific benefit of the
MedDiet. Future trials with longer follow-up are needed
to confirm the hypothesis that the MedDiet may be
superior to other dietary interventions to improve
kidney function.
Besides the limited duration of follow-up, our study
has other limitations. First, the study sample consisted
of older Mediterranean white individuals at high risk of
coronary heart disease, which prevents generaliza-tion
of results to other age groups or ethnicities. Second,
kidney function markers were determined at baseline
and 1 year of intervention only once, and the known
biological variability of these measurements may have
led to some degree of misclassification. However,
measurements were done in a core labora-tory, thus
reducing variability. Third, in our study, mean eGFR at
baseline was fairly high compared with other healthy
populations,42 which may have pre-cluded the
observation of clinically significant changes in kidney
parameters and limited the number of clini-

Am J Kidney Dis. 2012;60(3):380-389 387


cal outcomes. Fourth, many of our patients were
using drugs that have a direct effect on kidney
function. To minimize this effect, we adjusted our
analyses by the use of medication with known effects
on kidney function. Fifth, unfortunately, we did not
directly measure GFR from creatinine clearance rate.
Finally, the equation used to estimate GFR has not
been validated in obese people at high cardiovascular
risk; thus, it may not be the most appropriate for our
population.
In conclusion, our study did not provide enough
evidence to support a superiority of one diet over
another. Absence of evidence does not mean
evidence of no effect.43 Only equivalence trials are
properly suited to demonstrate equality of effects.44
ACKNOWLEDGEMENTS
In addition to the named authors, the PREDIMED-Reus Investi-
gators include Nancy Babio, Cristina Molina, Teresa Basora, Juanjo
Cabré, Bernardo Costa, Joaquim Garcia Roselló, Núria Ibarrola,
Fabiola Márquez, Ramón Segarra, and Sergio Rojas.
The authors thank the participants for their enthusiastic
collabo-ration, the PREDIMED personnel for excellent
assistance, the personnel of all affiliated primary care centers, and
Alberto Marti-nez-Vea (Nephrology Department, Joan XXIII
Hospital, Tarra-gona, Spain) for critical review of the manuscript.
Support: This study was funded in part by the Spanish Ministry
of Health (Instituto de Salud Carlos III [ISCIII]), PI1001407,
G03/140, RD06/0045, FEDER (Fondo Europeo de Desarrollo
Regional), the Public Health Division of the Department of
Health of the Autonomous Government of Catalonia, and Caixa
Tarra-gona (10-1343). The Fundación Patrimonio Comunal
Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut
Commis-sion (Sacramento, CA), Borges SA (Reus, Spain), and
Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts,
almonds, and hazelnuts, respectively, used in the PREDIMED
Study. None of the funding sources had a role in the design,
collection, analysis, or interpretation of data or in the decision to
submit the manuscript for publication. CIBER Fisiopatología de
la Obesidad y Nutrición (CIBERobn) is an initiative of ISCIII.
Financial Disclosure: Dr Salas-Salvadó is a nonpaid member
of the Scientific Advisory Board of the International Nut Council,
Reus, Spain. Dr Ros is a nonpaid member of the Scientific
Advisory Committee of the California Walnut Commission,
Sacra-mento, CA. The other authors declare that they have no
relevant financial interests.
SUPPLEMENTARY MATERIAL
Table S1: Changes in kidney function from baseline to 1 year
of dietary intervention in participants with or without type 2
diabetes mellitus at baseline.
Table S2: Changes in kidney function from baseline to 1 year
of dietary intervention in individuals with or without eGFR 60.
Note: The supplementary material accompanying this article
(http://dx.doi.org/10.1053/j.ajkd.2012.02.334) is available at
www.ajkd.org
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