ORIGINAL INVESTIGATIONS

Pathogenesis and Treatment of Kidney Disease and Hypertension

A Central Body Fat Distribution Is Related to Renal Function

Impairment, Even in Lean Subjects
Sara-Joan Pinto-Sietsma, MD, PhD, Gerjan Navis, MD, PhD, Wilbert M.T. Janssen, MD, PhD,
Dick de Zeeuw, MD, PhD, Reinhold O.B. Gans, MD, PhD, and
Paul E. de Jong, MD, PhD, for the PREVEND Study Group

● Background: Overweight and obesity are believed to be associated with renal damage. Whether this depends on
fat distribution is not known. We hypothesize that in addition to overweight, fat distribution may be associated with
renal function abnormalities. Methods: We studied the relation between body weight and fat distribution and
microalbuminuria and elevated or diminished filtration in 7,676 subjects without diabetes. Microalbuminuria is
defined as urinary albumin excretion (UAE) of 30 to 300 mg/24 h. Elevated and diminished filtration are defined as
filtration plus or minus 2 SDs of a nondiabetic lean group with a peripheral fat distribution and UAE of 0 to 15 mg/24
h, corrected for age and sex. The total population was divided into six groups according to body weight (overweight
is defined as body mass index [BMI] > 25 and < 30 kg/m2; obesity, as BMI > 30 kg/m2) and fat distribution. Results:
In logistic regression analysis, obese subjects with central fat distribution had a greater risk for microalbuminuria
(relative risk, 1.7; 95% confidence interval, 1.19 to 2.35). Obese subjects with either peripheral or central fat
distribution had a greater risk for elevated filtration (relative risk, 3.2; 95% confidence interval, 1.19 to 8.47; relative
risk, 2.6; 95% confidence interval, 1.59 to 4.28, respectively). Furthermore, subjects with central fat distribution,
either lean, overweight, or obese, had a greater risk for diminished filtration (relative risk, 1.9; 95% confidence
interval, 1.19 to 3.12; relative risk, 2.0; 95% confidence interval, 1.19 to 3.19; and relative risk, 2.7; 95% confidence
interval, 1.46 to 4.85, respectively). Finally, by dividing waist-hip ratio (WHR) into quartiles, greater WHR was
associated with a greater risk for diminished filtration, even when corrected for BMI. Conclusion: Not only
overweight and obese subjects, but also lean subjects with central fat distribution are at risk for diminished
filtration. Therefore, a central pattern of fat distribution, not overweight or obesity by itself, seems to be important
for renal impairment. Am J Kidney Dis 41:733-741.
© 2003 by the National Kidney Foundation, Inc.

INDEX WORDS: Overweight; obesity; central fat distribution; renal function; renal impairment; microalbuminuria

T HE PREVALENCE of overweight and obe-

sity, defined according to World Health
Organization criteria1 as a body mass index (BMI)
more than 25 kg/m2 and more than 30 kg/m2,
respectively, appears to be steadily increasing.2
Because excess weight gain initiates a cascade of
metabolic, endocrine, cardiovascular, and renal
changes, obesity is a major health problem.
The impact of obesity on renal function has
been investigated over the years. Obesity is asso-
ciated with both renal hyperfiltration3-5 and hyper-
perfusion6 and microalbuminuria.7 Moreover,
experimental observations of an increased glo-
merular filtration rate, mainly in superficial
nephrons and in association with expansion of
glomerular area and mesangial matrix, were made
in Zucker rats with genetic obesity.8 Later, glo-
merular filtration rate tends to normalize and
subsequently decreases, together with the devel-
opment of progressive albuminuria and glomeru-
losclerosis.9,10
Also from human studies, it has been argued
that overweight may lead to end-stage renal
disease. For instance, focal glomerular sclerosis
and/or diabetic nephropathy have been observed
in massive obese patients who presented with
proteinuria.11 Recently, Praga et al12 showed that
From the Department of Internal Medicine, Division of
Nephrology, University Hospital Groningen; and Depart-
ment of Clinical Pharmacology, University Groningen, and
Groningen University Institute for Drug Exploration, Gro-
ningen, The Netherlands
Received June 14, 2002; accepted December 17, 2002.
For the Prevention of Renal and Vascular End-Stage
Disease (PREVEND) Study Group (see Appendix).
Supported in part by grant no. E033 from the Dutch
Kidney Foundation.
Address reprint requests to Sara-Joan Pinto-Sietsma, MD,
PhD, Department of Internal Medicine, University Hospital
Maastricht, P Debeyelaan 25, 6202 AZ Maastricht, The
Netherlands. E-mail: pintosj@hotmail.com
© 2003 by the National Kidney Foundation, Inc.
0272-6386/03/4104-0001$30.00/0

American Journal of Kidney Diseases, Vol 41, No 4 (April), 2003: pp 733-741 733
734
obese subjects were more at risk to develop
proteinuria and renal failure after unilateral ne-
phrectomy than nonobese subjects.
However, there is evidence that not over-
weight or obesity per se, but distribution of body
fat, is related to a variety of physiological aberra-
tions. Central body fat distribution is related to
hyperinsulinemia, hypertension, hyperlipidemia,
and atherosclerosis.13,14 Interestingly, in a small
study, Scaglione et al15 also showed that subjects
with central fat distribution had reduced renal
plasma and blood flow and increased filtration
fraction and albuminuria, whereas this could not
be observed in subjects with peripheral fat distri-
bution. Conversely, these were both normoten-
sive and hypertensive subjects, and no compari-
son was made with lean subjects with central fat
distribution.
We therefore hypothesized that central fat dis-
tribution, whether in lean, overweight, or obese
subjects, is related to such renal abnormalities as
microalbuminuria and elevated and diminished
filtration in a nondiabetic population. To test this
hypothesis, we studied the cross-sectional rela-
tion between body weight and body fat distribu-
tion with albuminuria and creatinine clearance in
a large cohort collected to study causes and
consequences of microalbuminuria in subjects
without diabetes.
METHODS
Study Population
This study is part of the ongoing Prevention of Renal and
Vascular End-Stage Disease (PREVEND) study in the city
of Groningen, The Netherlands. All inhabitants aged 28 to
75 years (n ⫽ 85,421) were asked to send in a morning urine
sample and fill out a short questionnaire on demographics
and cardiovascular history. A total of 40,856 subjects (47.8%)
responded. Our actual study cohort was drawn from this
cohort based on all subjects with a urinary albumin concen-
tration of 0.10 g/dL or greater (ⱖ1.0 g/L; n ⫽ 7,768) in their
morning urine sample and a randomly selected control group
with a urinary albumin concentration less than 10 mg/L (n ⫽
3,395). Details of this protocol have been described else-
where.16
In total, 11,163 subjects were invited to the outpatient
clinic, of whom 8,592 subjects completed the screening
program. Subjects on insulin therapy or pregnant women
were excluded from participation in this screening program.
Our total population consisted mainly of Caucasian subjects.
Only 68 subjects (0.9%) were black and 163 subjects (2.1%)
were Asian. These groups were too small for a separate
analysis. The study was approved by the medical ethics
PINTO-SIETSMA ET AL
committee and conducted in accordance with the guidelines
of the Declaration of Helsinki. All participants attending the
outpatient clinic gave written informed consent.
Study Design
The screening program in the outpatient clinic consisted
of two visits. At the first visit, participants completed a
self-administered questionnaire regarding demographics, car-
diovascular and renal history, and drug use. After removal of
shoes and heavy clothing, weight was measured to the
nearest 0.5 kg using a Seca balance scale (Seca Vogel &
Halke GmbH & Co, Hamburg, Germany). Height was mea-
sured to the nearest 0.5 cm. Minimal waist circumference
was measured on bare skin at the natural indentation be-
tween the 10th rib and iliac crest. Hip circumference was
measured at the maximum circumference of the buttocks.17
At both visits, blood pressure was measured in supine
position every minute for 10 and 8 minutes (respectively)
using an automatic Dinamap XL model 9300 series monitor
(Critikon, Tampa, FL).
Subjects were asked to collect 24-hour urine samples on 2
consecutive days in the last week before the second visit.
Subjects were given oral and written instructions on how to
collect 24-hour urine samples and instructed to postpone
urine collection in case of fever, urinary tract infection, or
menstruation and refrain as far as possible from heavy
exercise during the collection period. Furthermore, subjects
were asked to store the urine cold (4°C) for a maximum of 4
days before the second visit. Measurements of urinary vol-
ume and albumin and creatinine concentrations were per-
formed on each collection. At the second visit, blood was
drawn after an overnight fast for determination of plasma
glucose and serum creatinine and cholesterol levels.
Calculations
Systolic and diastolic blood pressures were calculated as
the mean of the last two measurements of the two visits
(systolic blood pressure range, 85 to 239 mm Hg; diastolic
blood pressure range, 47 to 114 mm Hg). BMI was calcu-
lated as the ratio between weight (kilograms) and the square
of height (in meters; weight/height2; BMI range, 16.31 to
63.61 kg/m2). Waist-hip ratio (WHR) was calculated as the
ratio between minimal waist circumference (centimeters)
and hip circumference (centimeters; WHR range, 0.45 to
1.39). Body surface area was calculated according to DuBois
and DuBois.18 Creatinine clearance is defined as the mean of
two creatinine clearances based on 24-hour urinary creati-
nine excretions divided by plasma creatinine level and
corrected for body surface area (creatinine clearance range,
12.72 to 257.34 mL/min/1.73 m2 [0.21 to 4.30 mL/s/1.73
m2]). Urinary albumin excretion (UAE) is given as the mean
of two 24-hour urine excretions (UAE range, 1.0 to 4,710.0
mg/24 h).
Laboratory Methods
Urinary albumin concentration was determined by neph-
elometry, with a threshold of 0.023 g/dL (0.23 g/L) and
intra-assay and interassay coefficients of variation of 4.3%
or less and 4.4% or less, respectively (Dade Behring Diag-
nostic, Marburg, Germany). Plasma glucose, serum choles-
CENTRAL FAT DISTRIBUTION AND RENAL FUNCTION
terol, and serum and urinary creatinine levels were deter-
mined using Kodak Ektachem dry chemistry (Eastman
Kodak, Rochester, NY). Urinary leukocyte and erythrocyte
measurements were performed using Nephur-test⫹leuco
sticks (Boehringer Mannheim, Mannheim, Germany).
Data Handling and Definitions
In the present analysis, we excluded 433 subjects because
of erythrocyturia or leukocyturia (erythrocytes ⬎ 50 cells/
&muL, leukocytes ⬎ 75 cells/&muL, or leukocytes of 75
cells/&muL and erythrocytes ⬎ 5 cells/&muL). In addition,
301 subjects were excluded because they had non–insulin-
dependent diabetes. Diabetes is defined as a fasting plasma
glucose level of 126.13 mg/dL or greater (ⱖ7.0 mmol/L),
nonfasting plasma glucose level of 200 mg/dL or greater
(ⱖ11.1 mmol/L), or use of oral antidiabetic drugs. Finally,
182 subjects were excluded because of missing data. Alto-
gether, 7,676 subjects were eligible for this analysis.
We differentiated subjects with central or peripheral fat
distribution by using WHR. Central fat distribution is de-
fined as a WHR of 0.9 or greater for men and 0.8 or greater
for women, and peripheral fat distribution, a WHR less than
0.9 for men and less than 0.8 for women.19 Lean is defined as
a BMI of 25 kg/m2 or less, overweight is defined1 as a BMI
greater than 25 and 30 kg/m2 or less, and obesity is defined
as a BMI greater than 30 kg/m2.
We divided our study population into six groups accord-
ing to BMI and WHR. Group 1 included lean subjects with
peripheral fat distribution; group 2, lean subjects with cen-
tral fat distribution; group 3, overweight subjects with periph-
eral fat distribution; group 4, overweight subjects with
central fat distribution; group 5, obese subjects with periph-
eral fat distribution; and group 6, obese subjects with central
fat distribution.
Furthermore, microalbuminuria is defined according to
the classic definition of albumin of 30 to 300 mg/24 h.
Elevated and diminished filtration are defined as a creati-
nine clearance ⫾ two times the SD of the creatinine clear-
ance regression line of a group of nondiabetic, peripheral,
lean control subjects with UAE of 0 to 15 mg/24 h.16 The
creatinine clearance regression line with the two times SD
borders was obtained by means of linear regression analysis
adjusted for age and sex. Hypercholesterolemia is defined as
a plasma cholesterol level greater than 250.97 mg/dL (6.5
mmol/L) or greater than 193.05 mg/dL (5.0 mmol/L) in case
of a previous myocardial infarction. Hypertension is defined
as systolic blood pressure of 160 mm Hg or greater, diastolic
blood pressure of 95 mm Hg or greater, or use of antihyper-
tensive medication. Smokers are defined as currently smok-
ing, and nonsmokers, as never having smoked.
Statistical Analysis
All calculations were performed using SPSS, version 9.0
(SPSS Inc, Chicago, IL) software. Continuous data are
reported as mean ⫾ SD. In case of skewed distribution,
median with 25th and 75th percentiles was presented. Differ-
ences among the six groups were assessed using chi-square
analysis or analysis of variance. All P are two tailed. P less
than 0.05 is considered statistically significant.
The linear regression model used to define elevated and
735
diminished filtration was performed in the following way.
First, of the total population, we selected two control or
healthy subgroups that consisted of either male or female
nondiabetic lean control subjects with peripheral fat distribu-
tion and UAE of 0 to 15 mg/24 h. In a linear regression
model with creatinine clearance corrected for body surface
area as the dependent variable and age as the independent
variable, we constructed a regression line of creatinine
clearance for men and women separately. Because each of
these two subgroups showed a normal distribution concern-
ing creatinine clearance corrected for body surface area, we
used the two times SD borders of this regression line of
creatinine clearance to define elevated and diminished filtra-
tion.20
To investigate the risk between overweight in combina-
tion with fat distribution and microalbuminuria and both
elevated and diminished filtration, we used a logistic regres-
sion model. We first performed a crude analysis. Second,
because fat distribution is highly related to sex, we tested
whether there was a sex-independent relation between over-
weight in combination with fat distribution and microalbu-
minuria and both elevated and diminished filtration. There-
fore, we analyzed data only by adjusting for sex to be able to
get insight on the influence of sex in the model. Third, odds
ratios were calculated after adjustment for other possible
confounding factors, such as age, smoking, systolic and
diastolic blood pressure, use of antihypertensive medication,
serum cholesterol level, lipid-lowering medication, and
plasma glucose level. Calculated odds ratios and 95% confi-
dence intervals are expressed as an approximation of relative
risk.
RESULTS
Table 1 lists unadjusted population characteris-
tics according to body weight and fat distribu-
tion. All groups with central fat distribution were
more often men, older, had higher blood pressure
and glucose levels, a greater percentage of sub-
jects with hypertension, and a greater percentage
of subjects with hypercholesterolemia, com-
pared with lean control subjects with peripheral
fat distribution. Overweight subjects with central
fat distribution were more often men, older, had
higher blood pressure and glucose levels, and a
greater percentage of subjects with hypertension
or hypercholesterolemia compared with lean sub-
jects with central fat distribution. Obese subjects
with central fat distribution had a greater glucose
and cholesterol level and greater percentage of
subjects with hypertension compared with lean
and overweight subjects with central fat distribu-
tion.
Concerning renal parameters, lean and over-
weight subjects with central fat distribution had
greater UAE, a greater percentage of subjects
with microalbuminuria, and a lower creatinine
736 PINTO-SIETSMA ET AL

Table 1. Population Characteristics According to Body Weight and Fat Distribution

Lean Overweight Obese

Fat
Distribution Peripheral Central Peripheral Central Peripheral Central

No. of patients (%) 2,033 (26.8) 1,406 (18.5) 654 (8.6) 2,398 (31.6) 103 (1.4) 993 (13.1)
Men (%) 42.9 47.4* 48.9* 63.2*†‡ 20.4* 51.2*§㛳
Age (y) 42 ⫾ 10 48 ⫾ 12* 45 ⫾ 12* 53 ⫾ 12*†‡ 49 ⫾ 13* 53 ⫾ 12*†‡
BMI (kg/m2) 22.17 ⫾ 1.75 23.04 ⫾ 1.50* 26.65 ⫾ 1.27* 27.26 ⫾ 1.39*†‡ 32.86 ⫾ 3.19* 33.22 ⫾ 3.46*†‡§
WHR 0.79 ⫾ 0.06 0.90 ⫾ 0.07* 0.81 ⫾ 0.06* 0.93 ⫾ 0.07*†‡ 0.78 ⫾ 0.06 0.95 ⫾ 0.08*†‡§㛳
SBP (mm Hg) 118 ⫾ 15 124 ⫾ 18* 127 ⫾ 17* 135 ⫾ 20*†‡ 131 ⫾ 20* 140 ⫾ 20*†‡§㛳
DBP (mm Hg) 69 ⫾ 9 72 ⫾ 9* 73 ⫾ 9* 77 ⫾ 9*†‡ 72 ⫾ 10* 78 ⫾ 10*†‡㛳
Hypertension (%) 10.2 21.3* 24.2* 42.4*†‡ 34.0* 54.9*†‡§㛳
Serum cholesterol 201.16 ⫾ 40.54 215.44 ⫾ 42.86* 214.67 ⫾ 42.47* 226.25 ⫾ 42.86*†‡ 218.92 ⫾ 42.08* 230.50 ⫾ 41.31*†‡§
(mg/dL)
Hypercholesterolemia (%) 12.7 25.5* 18.2* 32.1*†‡ 21.4* 33.8*†‡㛳
Glucose (mg/dL) 79.28 ⫾ 9.01 82.88 ⫾ 10.81* 82.88 ⫾ 10.81* 88.23 ⫾ 10.81*†‡ 86.47 ⫾ 12.61* 91.89 ⫾ 12.61*†‡§㛳
Smoking (%) 53.7 62.2* 41.4* 53.6†‡ 35.5* 50.3†‡㛳
UAE (mg/24 h) 7.9 (5.8–12.5) 8.4 (6.0–13.5)* 8.1 (6.1–12.4)* 10.2 (6.5–20.6)*†‡ 8.5 (6.1–16.3) 12.6 (7.7–29.2)*†‡§
Microalbumaria (%) 6.7 8.9* 6.3 15.9*†‡ 13.6* 21.2*†‡§
Serum creatinine 0.92 ⫾ 0.19 0.93 ⫾ 0.18 0.95 ⫾ 0.16* 0.98 ⫾ 0.19*†‡ 0.89 ⫾ 0.16 0.97 ⫾ 0.17*†㛳
(mg/dL)
Creatinine clearance 94.97 ⫾ 19.02 92.20 ⫾ 20.40* 95.02 ⫾ 21.07* 91.14 ⫾ 21.38*‡ 91.81 ⫾ 21.12 93.00 ⫾ 22.97
mL/min/1.73 (m2)
EF (%) 2.9 4.0 4.6* 3.8* 4.9 6.8*†§
DF (%) 2.8 3.5 2.8 3.4 1.9 3.9

NOTE. Values expressed as mean ⫾ SD, except for UAE, expressed as median (25th to 75th percentiles). Conversion
factors from conventional to SI units for cholesterol, glucose, and serum creatinine are 0.0259 0.0555, and 88.4, respectively.
Abbreviations: EF, elevated filtration; DF, diminished filtration; SBP, systolic blood pressure; DBP, diastolic blood
pressure; UAE, urinary albumin excretion.
*P ⬍ 0.05 versus lean control subjects with peripheral fat distribution.
†P ⬍ 0.05 versus lean subjects with central fat distribution.
‡P ⬍ 0.05 versus overweight subjects with peripheral fat distribution.
§P ⬍ 0.05 versus overweight subjects with central fat distribution.
㛳P ⬍ 0.05 versus obese subjects with peripheral fat distribution.

clearance compared with lean and overweight
subjects with peripheral fat distribution. Concern-
ing obese subjects with central fat distribution,
except for serum creatinine level, there was no
significant difference compared with obese sub-
jects with peripheral fat distribution. Further-
more, overweight subjects with central fat distri-
bution had greater UAE and a greater percentage
of subjects with microalbuminuria compared with
lean subjects with central fat distribution. Obese
subjects with central fat distribution had greater
UAE, a greater percentage of subjects with mi-
croalbuminuria, and elevated filtration compared
with both the lean and overweight group with
central fat distribution.
Because Table 1 shows only the crude differ-
ence among the six groups without statistical
corrections, we are not allowed to draw conclu-
sions at this point. Table 1 only provides us
insight in possible differences or confounders
among the six groups. To correct for these differ-
ences, we also analyzed our data in a logistic
regression model with microalbuminuria and both
elevated and diminished filtration as dependent
variables.
First, we analyzed the crude relation between
overweight and renal abnormalities, such as mi-
croalbuminuria and both elevated and dimin-
ished filtration (Tables 2, 3, and 4). Second,
because it seems obvious that sex acts as a
confounder on overweight and fat distribution,
which also can be concluded from Table 1, we
assessed the impact of sex on overweight and fat
distribution in a logistic regression analysis. We
therefore analyzed our data with and without
adjusting for sex, which did not severely change
the model (Tables 2, 3, and 4). Furthermore, sex
did not act as an interaction term when used as
such in the models and therefore did not influ-
ence results.
CENTRAL FAT DISTRIBUTION AND RENAL FUNCTION 737

Table 2. Adjusted Relative Risks for Microalbuminuria According to Body Weight and Fat Distribution

Microalbuminuria

Crude Relative Risk Sex Relative Risk Confounder Relative Risk

Lean
Peripheral 1.0* 1.0* 1.0*
Central 1.4 (1.09–1.81)† 1.4 (1.06–1.77) 0.7 (0.51–1.00)
Overweight
Peripheral 0.9 (0.65–1.35) 0.9 (0.63–1.30) 0.6 (0.38–1.02)
Central 3.0 (2.40–3.64)* 2.6 (2.14–3.25)* 1.0 (0.73–1.31)
Obese
Peripheral 2.2 (1.23–4.03)† 2.7 (1.46–4.86)† 1.2 (0.50–2.85)
Central 4.6 (3.62–5.80)* 4.5 (3.52–5.66)* 1.7 (1.19–2.35)†

NOTE. Adjusted for the confounders age, sex, systolic and diastolic blood pressure, antihypertensive medication, serum
cholesterol level, lipid-lowering medication, plasma glucose level, and smoking. Relative risks and 95% confidence intervals
are for lean subjects with central fat distribution, overweight subjects with a peripheral fat distribution, overweight subjects
with central fat distribution, obese subjects with peripheral fat distribution, and obese subjects with central fat distribution
compared with lean control subjects with peripheral fat distribution. The significance given in the group with lean control
subjects with peripheral fat distribution refers to the overall significance of the adjusted model, with symbols representing the
significance as stated before.
*P ⬍ 0.001.
†P ⬍ 0.01.

Finally, we assessed whether there was an
independent relation between overweight and
renal abnormalities. Therefore, in addition to
sex, we adjusted for age, systolic and diastolic
blood pressure, antihypertensive medication, se-
rum cholesterol level, lipid-lowering medication,
glucose level, and smoking. These were all con-
founders, as observed from Table 1. Subjects
with central fat distribution, whether they were
lean, overweight, or obese, showed an indepen-
dent greater risk for diminished filtration (Table
4). Obese subjects with and without central fat

Table 3. Adjusted Relative Risks for Elevated Filtration According to Body Weight and Fat Distribution

Elevated Filtration

Crude Relative Risk Sex Relative Risk Confounder Relative Risk

Lean
Peripheral 1.0* 1.0* 1.0†
Central 1.4 (0.98–2.07) 1.4 (0.99–2.08) 1.2 (0.77–1.92)
Overweight
Peripheral 1.6 (1.04–2.56)‡ 1.7 (1.05–2.59)‡ 1.7 (1.00–2.98)
Central 1.3 (0.96–1.88) 1.4 (0.99–1.96) 1.4 (0.87–2.12)
Obese
Peripheral 1.7 (0.67–4.35) 1.6 (0.64–4.19) 3.2 (1.19–8.47)‡
Central 2.5 (1.74–3.58)* 2.5 (1.77–3.64)* 2.6 (1.59–4.28)*

NOTE. Adjusted for the confounders age, sex, systolic and diastolic blood pressure, antihypertensive medication, serum
cholesterol level, lipid-lowering medication, plasma glucose level, and smoking. Relative risks and 95% confidence intervals
are for lean subjects with central fat distribution, overweight subjects with peripheral fat distribution, overweight subjects with
central fat distribution, obese subjects with peripheral fat distribution, and obese subjects with central fat distribution
compared with lean control subjects with peripheral fat distribution. The significance given in the group with lean control
subjects with peripheral fat distribution refers to the overall significance of the adjusted model, with the symbols representing
the significance as stated before.
*P ⬍ 0.001.
†P ⬍ 0.01.
‡P ⬍ 0.05.
738 PINTO-SIETSMA ET AL

Table 4. Adjusted Relative Risks for Diminished Filtration According to Body Weight and Fat Distribution

Diminished Filtration

Crude Relative Risk Sex Relative Risk Confounder Relative Risk

Lean
Peripheral 1.0 1.0 1.0‡
Central 1.3 (0.87–1.91) 1.3 (0.87–1.90) 1.9 (1.19–3.12)
Overweight
Peripheral 1.0 (0.59–1.74) 1.0 (0.59–1.73) 1.3 (0.67–2.70)
Central 1.2 (0.88–1.76) 1.2 (0.86–1.74) 2.0 (1.19–3.19)†
Obese
Peripheral 0.7 (0.17–2.94) 0.7 (0.17–2.99) 0.01 (0.00–⬎100)
Central 1.5 (0.97–2.23) 1.5 (0.96–2.22) 2.7 (1.46–4.85)‡

NOTE. Adjusted for the confounders age, sex, systolic and diastolic blood pressure, antihypertensive medication, serum
cholesterol level, lipid-lowering medication, plasma glucose level, and smoking. Relative risks and 95% confidence intervals
are for lean subjects with central fat distribution, overweight subjects with peripheral fat distribution, overweight subjects with
central fat distribution, obese subjects with peripheral fat distribution, and obese subjects with central fat distribution
compared with lean control subjects with peripheral fat distribution. The significance given in the group with lean control
subjects with peripheral fat distribution refers to the overall significance of the adjusted model, with symbols representing the
significance as stated before.
†P ⬍ 0.01.
‡P ⬍ 0.05.

distribution showed an independent greater risk
for elevated filtration (Table 3). Furthermore,
obese subjects with central fat distribution also
showed an independent greater risk for microalbu-
minuria (Table 2). All analyses were performed
in comparison to lean control subjects with per-
ipheral fat distribution.
Because from these data, central fat distribu-
tion, not just overweight or obesity, seems impor-
tant for diminished filtration, we were interested
in whether there would be a linear relation be-
tween WHR and diminished filtration indepen-
dent of obesity. Therefore, we analyzed our data
in a logistic regression analysis with diminished
filtration as the dependent variable and WHR in
quartiles. Figure 1 shows a linear relation be-
tween WHR and diminished filtration, even when
adjusted for such confounders as age, sex, sys-
tolic and diastolic blood pressure, antihyperten-
sive medication, serum cholesterol level, lipid-
lowering medication, glucose level, smoking,
and BMI (P ⬍ 0.01 for the overall model).
Again, sex could act as a major confounder,
but by analyzing our model with and without
correcting for sex, results remained similar. In
addition, we analyzed our data split for both sex
groups, which gave similar results. We also ana-
lyzed our data in a linear regression model that
showed WHR was more important for dimin-
ished filtration (Wald statistic, 5.38; P ⬍ 0.02)
than BMI (Wald statistic, 2.83; P ⫽ not signifi-
cant), which is in agreement with our results.
DISCUSSION
This study shows that subjects with central fat
distribution, whether they are lean, overweight,
or obese, have a greater risk for diminished
filtration. This effect even seems dose dependent
in a way that with increasing WHR, risk for
diminished filtration increases. Obese subjects
with and without central fat distribution have a
greater risk for elevated filtration. Furthermore,
obese subjects with central fat distribution also
showed a greater risk for microalbuminuria. In-
terestingly, fat distribution and diminished filtra-
tion appear to be linearly related to one another.
From our data, it seems that fat distribution may
be of more importance for renal impairment than
overweight or obesity by itself. By dividing our
data into six groups, we lose power, especially in
the group of obese subjects with peripheral fat
distribution, making it harder to interpret.
What could be the underlying mechanism that
makes subjects with central fat distribution more
prone to impaired renal function? There is strong
evidence that central body fat distribution is
related to insulin resistance.13,21 Furthermore,
greater insulin and glucagon levels were found in
CENTRAL FAT DISTRIBUTION AND RENAL FUNCTION
Fig 1. Relative risk and
95% confidence intervals for
diminished filtration among
quartiles of WHR. P < 0.01
for the overall model, cor-
rected for such confounders
as age, sex, systolic and
diastolic blood pressure, an-
tihypertensive medication,
serum cholesterol level,
lipid-lowering medication,
plasma glucose level, smok-
ing, and BMI.
patients with central compared with peripheral
fat distribution.22 It has been suggested that both
insulin and glucagon, by means of their effects
on renal hemodynamics, may influence glomeru-
lar filtration rate and albuminuria.23-25 Because
we did not measure insulin levels, we are not
entitled to make a statement about insulin resis-
tance in our subjects with central fat distribution.
Conversely, clustering of such features of meta-
bolic syndrome as hypertension, high plasma
glucose level, hypercholesterolemia, and greater
UAE could be observed, particularly in our sub-
jects with central fat distribution.
Hyperfiltration is a frequent early finding in
patients with diabetes26 and a possible predictor
of the subsequent development of microalbumin-
uria and ultimate diabetic nephropathy.27 Hyper-
filtration also has been shown in obese sub-
jects,3-5 suggesting that also in obesity,
hyperfiltration might precede renal function loss.
However, in lean subjects with central fat distri-
bution, no such increased risk for hyperfiltration
could be detected.
An important question is whether sex effects
on obesity and fat distribution could influence
our results. Because we did not find a significant
univariate relation between renal function and
sex, we doubted whether sex would yield a major
influence on renal function in our analysis. In
739
addition, as listed in Tables 3 and 4, the model
remained similar with and without correcting for
sex. Finally, we also analyzed our data in a split
database for men and women separately. There
was no difference in outcomes between analysis
of the split database and multivariate analysis.
We therefore conclude that sex is no true con-
founder in this analysis.
One might argue that by using categorical
variables, arbitrary cutoff points are being intro-
duced. However, we used generally accepted
cutoff levels according to the literature and clini-
cal practice. We therefore prefer to present the
data in this way because it is easier to interpret
and also accessible for the more clinically inter-
ested reader. We also analyzed WHR linearly by
analyzing our data with WHR in quartiles; this
showed a linear relationship between WHR and
diminished filtration.
The question is whether these renal function
abnormalities in relation to fat distribution are
caused by the accompanying hypertension and
diabetes so frequently present in obese subjects.
Subjects with central fat distribution had higher
blood pressure and glucose levels. No clinical
studies to date have tried to establish an indepen-
dent relation between overweight and renal abnor-
malities. Our study gives us the opportunity to
investigate the independent relation between cen-
740
tral fat distribution and renal function abnormali-
ties because it is a large population-based study
and therefore suitable for correcting for such
confounders as hypertension and diabetes. We
chose to correct for diabetes by selecting a non-
diabetic population.
Conversely, because diabetes is a continuum
and there exists a state of prediabetes, often
associated with central obesity, we also corrected
for plasma glucose level. Furthermore, we cor-
rected not only for blood pressure level, but also
for antihypertensive treatment. Interestingly, our
study showed a positive relation between fat
distribution and renal function that was indepen-
dent of hypertension and diabetes.
We corrected creatinine clearance for body
surface area because the impact of body compo-
sition on renal function is known. It has been
suggested that correcting for body surface area
might give inappropriately low values of renal
plasma flow in obese subjects.15 Therefore, part
of the obese group might be in the group with
diminished filtration, thereby influencing results.
We do not believe this is the case because obese
subjects tend to have a greater filtration rate than
normal, and by correcting their renal function for
body surface area, their renal function will return
to normal. Furthermore, the group with dimin-
ished filtration had a mean creatinine clearance
of approximately 50 mL/min/1.73 m2, which
shows that their renal function really is compro-
mised.
As described by Turner and Reilly,28 we also
analyzed our data by introducing weight and
height as dependent variables in the model. This
gave similar results. Also, by changing our model
by omitting or reentering one of the other vari-
ables, results remained similar.
Caution should be applied when interpreting
our data because this is only a cross-sectional
study. Cross-sectional studies render the opportu-
nity to investigate more risky hypotheses without
the efforts and costs of follow-up studies. At
present, these subjects are followed up for
changes in renal function. Such data will be
needed to confirm our present observation.
In conclusion, subjects with central fat distri-
bution are at risk for renal function impairment
independent of blood pressure and plasma glu-
cose levels. This might indicate that fat distribu-
tion is important for renal function abnormali-
PINTO-SIETSMA ET AL
ties, not just whether a subject is overweight or
obese.
ACKNOWLEDGMENT
The authors thank research nurses Roelie Dijkstra-
Oppenhuizen and Erika Konneman-van Zalk for assistance
at the outpatient clinic; Winie G.A. de Jonge-Hovenkamp
for secretarial assistance; Dr Enno van der Veur (General
Practitioners Laboratory, Groningen) and Jacko J. Duker
(Nephrology Laboratory, University Hospital, Groningen)
for laboratory assistance; and Drs Frank P.G. Lambert and
Robert J. Bieringa (Trial Coordination Centre, Groningen)
for data handling.
APPENDIX
The PREVEND Study Group
In addition to the authors, PREVEND investi-
gators are: Andries J. Smit, MD, PhD (Depart-
ment of Internal Medicine); Harry J.G.M. Crijns,
MD, PhD, Ad J. van Boven, MD, PhD (Depart-
ment of Cardiology); Wiek H. Van Gilst, PhD,
Gilles F.H. Diercks, MD (Department of Clinical
Pharmacology); Lolkje T.W. de Jong-van den
Berg, PhD, Maarten Postma, PhD, Taco B.M.
Monster, MSc (Social Pharmacy and Pharmaco-
epidemiology); Gerard J. te Meerman, PhD (De-
partment of Medical Genetics), all from Univer-
sity Hospital Groningen, The Netherlands; and
Jan Broer, MD, PhD (Municipal Health Depart-
ment), Groningen, The Netherlands.
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