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From the Departments of Medicine and Radiology, Harvard Medical School
and Brigham and Women's Hospital, Boston, Mass.
Renal perfusion determination in humans is complicated by the widely
perceived need to index RBF to some measure of body
size.4 5 6 7 8 9 During human development, for example,
renal mass, perfusion, and function increase as the body grows from
infancy to the adult state. Moreover, in adults, renal mass does vary
with body mass.4 Thus, the need to normalize or
index renal perfusion for body size has been intuited as obvious.
Standard practice has been to use a body surface area of 1.73
m2 , a convention that is the subject of
substantial recent analysis.5 6 7 8 9
Depending on whether normalization for body surface area was used,
renal perfusion could be less than anticipated or exceed expectation.
Thus, at the moment there is no information in humans on either the
appropriate adjustment of renal perfusion for body mass or the
consequence of increase of obesity for renal perfusion.
To address these issues, we took advantage of the fact that radioactive
xenon (133Xe) transit through the kidney provides
a measure of blood flow per unit of tissue
mass.10 Because blood flow is registered as
milliliters per 100 grams per minute with this method, no further
adjustment for kidney size or body size is necessary. This method
requires injection of the tracer directly into the renal artery, which
we accomplished in potential kidney donors at the time of the renal
arteriogram that is required for kidney
donation.11 Although morbid obesity was
considered a contraindication to kidney
donation,12 subjects with moderate obesity did
undergo donor evaluation and arteriography, which made it possible to
assess the influence of obesity on renal tissue perfusion in otherwise
healthy humans. Also, because of our recent observation that obesity
blunts the renal vascular response to Ang II and also interacts
significantly with a common variant of the AGT gene to exert
an even greater blunting effect,5 we examined the
influence of salt intake on renal perfusion in obese and lean kidney
donors.
Renal perfusion in the obese subjects was compared with values from the
regression relationship between age and RBF in the 147 lean subjects as
reported previously (y=3.76-0.019x for low salt
intake; y=4.94-0.038x for high salt
intake).11 In addition, we were able to match 37
of the 45 obese subjects to 37 lean controls by age, gender, race, and
salt intake to examine metabolic status and blood pressure
in the obese subjects and appropriate matched control subjects.
Percutaneous selective renal arterial
catheterization and the determination of RBF with
133Xe have been described in
detail.15 Blood flow studies were initiated at
least 30 minutes after blood pressure stability was achieved following
aortography. An arterial blood sample was drawn for
measurement of PRA in 38 subjects just before blood flow
measurements.
Mean RBF was measured from the initial slope of
133Xe disappearance from the kidney, determined
graphically, with a hematocrit-corrected partition coefficient.
PRA was measured by radioimmunoassay of Ang I generated during a
30-minute incubation with endogenous substrate at
37°C.16 Creatinine concentration in
urine and serum was determined by the autoanalyzer method.
Sodium concentrations in urine and serum were measured by flame
photometry, with lithium as an internal standard.
Written consent was obtained from each subject after a detailed
description of the procedures. All protocols were approved by the Human
Experimentation Committees of the Brigham and Women's Hospital and
Harvard Medical School.
Data was expressed as mean values, and the SEM was used as the index of
dispersion. Regression analysis was performed with the SAS
statistical package. Statistical significance was assessed by
Wilcoxon signed-rank test for matched data and rank sum test
for unmatched data. The null hypothesis was rejected when
P<0.05.
In 21 obese subjects on low salt intake, age-adjusted renal
perfusion (352±16 mL · 100 g-1 ·
min-1) was significantly higher than that in
age-matched lean subjects (313±3 mL · 100
g-1 · min-1;
P=0.035) (Figure 1
Baseline PRA levels in obese and matched lean subjects on low salt
intake were not significantly different (2.7±0.4 and 3.2±0.3
µg · h-1 ·
L-1, respectively; P=0.112).
Similarly, basal PRA measured at the time of arteriography was
identical in the lean control (1.5±0.6 µg ·
h-1 · L-1) and
obese (1.5±0.5 µg · h-1 ·
L-1) subjects on a high salt diet (Table 3
Cut points to define obesity are problematic, since
cardiovascular risk increases with BMI in a continuous
manner. This has led to a range of definitions of obesity, with
somewhat arbitrary cut points. Many investigators have used the NHANES
II criteria defining "overweight" as a BMI
A potential limitation, limiting generalizability, but also a strength
of our study was the utilization of a relatively
homogeneous, very healthy population. Because these
individuals were being considered for kidney donation, only those
determined by exhaustive diagnostic evaluation to be free
of disease and at low risk underwent arteriography. For the same
reason, we were unable to study severely obese subjects. In a random
sample of obese patients in the community, one would expect a higher
blood pressure level and higher fasting blood sugar. In less healthy
obese subjects, increased body mass may exert a different effect on
renal perfusion.
Obesity-associated vasodilation has been demonstrated in animals in
relatively short-term overfeeding experiments. Dogs fed a high fat diet
for 6 weeks had increased cardiac output, decreased systemic vascular
resistance, and increased blood flow to the kidney and gastrointestinal
tract.2 Similar results were seen in rabbits
after 8 to 12 weeks of high fat intake.3 In both
normotensive and hypertensive obese humans, RBF was higher than in lean
controls,7 20 but when renal perfusion in humans
was normalized to body surface area, RBF fell with increasing
BMI.6 By using the radioxenon technique for
measuring RBF, we were able to eliminate considerations about either
body size or kidney size as relevant variables. Renal perfusion was
not reduced in obese humans, providing further evidence of the
inadequacy of normalizing RBF to body surface area.
Both the RAS and the actions of insulin have been considered candidates
in obesity-associated hemodynamic changes, but the
mechanisms remain unclear and all discussion must be considered
speculative. The fact that we found a salt intake–based difference in
the effect of obesity on RBF confirms, at least in part, the
interesting possibility of a role for the RAS. Measurement of PRA
levels in this study and elsewhere has not clarified this role. PRA has
been shown to be unchanged or increased in association with
obesity21 22 and may decrease with weight
loss.23 24 We found no significant difference in
PRA levels between obese and lean subjects in the present study.
This study was prompted in part by our recent finding that obesity is
associated with a blunted RBF response to infused Ang
II.5 In that study, designed to assess the effect
of AGT gene polymorphisms on Ang II–mediated control of
the renal circulation, obesity was found to be a strong predictor of
blunted renal response.5 The diminished response
seen in many hypertensive subjects was to a major degree accounted for
by their higher BMI. One possibility that we have considered is that
this blunted response in hypertension reflects downregulation of renal
Ang II receptors by chronically elevated intrarenal Ang II
levels.25 Downregulation of renal Ang II
receptors could also explain the failure of our obese subjects to
reduce their RBF appropriately in the setting of low salt intake.
Plasma AGT levels have repeatedly been shown to be strongly positively
correlated with BMI.26 27 28 AGT mRNA is expressed
abundantly in adipocytes.29 30 Expression varies
with fasting and refeeding in both normal rats and obese
mice.29 Plasma AGT concentration has been shown
repeatedly to vary directly with BMI in a variety of
populations26 27 28 and extended to the
demonstration of an association between AGT gene
polymorphisms and body fat distribution in
men.31
Our finding that the effect of obesity on renal perfusion was dependent
on sodium intake may be relevant to the complex relationship between
body weight and sodium sensitivity. When adolescents were changed from
a high salt to a low salt diet, only the obese group had a significant
change in blood pressure.32 Weight loss resulted
in a loss of BP sodium sensitivity even though ideal body weight was
not attained, suggesting that caloric excess rather than body weight
per se may determine sodium sensitivity. This has important
implications in extrapolation of results from short-term overfeeding
studies in animals to obese humans, who have likely been overweight for
a relatively long time. The fact that the high renal perfusion rates
were found primarily in young subjects (<31 years) in this study may
be relevant to the same issue.
Higher insulin levels associated with obesity also may contribute to
vasodilation. Hyperinsulinemic/euglycemic
clamp studies in normal humans revealed decreased forearm vascular
resistance and increased blood flow despite an increase in sympathetic
nerve activity.33 Peripheral
vasodilation was also demonstrated during chronic insulin infusions in
normal dogs.34 However, insulin infusions in dogs
that were insulin-resistant secondary to obesity failed to
cause vasodilation,1 and in obese humans, leg
blood flow increased with insulin infusion but at a much slower rate
than in lean humans.35 Fasting insulin levels in
obese humans were not correlated with RBF.7 This
lack of response in insulin-resistant individuals is
interesting in the light of the apparent effect of age in the
present study: the increase in RBF in the obese was most prominent
in the younger subjects (Figure 1
We believe that the findings in this study have two broad implications.
First, the renal vasodilation documented during short-term weight gain
caused by overfeeding in animal models can be identified in moderately
obese humans in the steady state and is not the product of
short-term overfeeding. Moreover, the degree of vasodilation varied
with the state of sodium balance, implicating RAS activation, possibly
at the tissue level. Finally, efforts to index renal perfusion to body
surface area may result in a systematic underestimation of renal
perfusion in the obese, an observation with ramifications for
interpretation of studies on the renal circulation in hypertension and
in non–insulin-dependent diabetes mellitus.
Received October 30, 1997;
first decision December 2, 1997;
accepted March 9, 1998.
© 1998 American Heart Association, Inc.
Scientific Contributions
Obesity, Salt Intake, and Renal Perfusion in Healthy Humans
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—Renal perfusion rises as
obesity develops during short-term overfeeding in animal studies. In
humans, the assessment is complicated by the need to normalize renal
perfusion for body size. We made use of the fact that radioactive xenon
washout measures renal perfusion per unit of tissue mass to address
this issue by comparing 45 moderately obese and 147 lean healthy
potential kidney donors. All were disease free. The rationale for
involving kidney donors reflects the fact that the xenon method for
measuring renal perfusion demands injection of the xenon directly into
the renal artery, which can be accomplished during the arteriogram that
is a necessary part of potential kidney donor evaluation. In 21 obese
subjects (body mass index [BMI], 29.1±0.9) in balance on a 10-mmol
sodium intake, renal perfusion (352±16 mL · 100
g-1 · min-1) was significantly higher
than predicted from findings in the 95 lean control subjects (313±3
mL · 100 g-1 · min-1;
P=0.035) after adjustment for age. With a high sodium
intake (200 mmol), however, renal perfusion was not significantly
different in 24 obese subjects (BMI, 28.8±0.7; 323±13 mL · 100
g-1 · min-1) in comparison to 52 lean
controls (341±10 mL · 100 g-1 ·
min-1) after adjustment for age. Systolic and
diastolic blood pressures were similar in obese and age-
and gender-matched lean control subjects. Renal vasodilation was seen
in association with sustained obesity in humans. While the mechanisms
of obesity-related vasodilation are unclear, the dependence on sodium
intake in this study is consistent with a role for the
renin-angiotensin system. The findings are not in
accordance with a reduction in renal perfusion reported in healthy
obese humans in whom measured renal perfusion was indexed for body
size.
Key Words: sodium • renin • renal blood flow
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Growing recognition
that obesity often plays a causal or complicating role in the
pathogenesis of hypertension and type 2 diabetes mellitus has led to
widespread interest in mechanisms that might link obesity with altered
renal function.1 Renal perfusion rises as obesity
develops during short-term overfeeding in dogs and
rabbits.2 3 In dogs, the increase in RBF occurs
without an increase in kidney weight, so perfusion increases per unit
of tissue mass.2 Kidney weight increases in
rabbits, however, and the rise in RBF with overfeeding is not
significant when adjusted for kidney mass.3
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
RBF studies with 133Xe were carried out at
the time of angiography in 192 potential kidney donors who ranged in
age from 18 to 63 years. The "lean" comparison group included 147
subjects whose body weight was within 20% of ideal according to
Metropolitan Life tables and who had a BMI <25. We defined "obese"
as a BMI >25.13 14 All subjects were admitted to
a metabolic ward where they were placed on a diet providing
a daily intake of either 10 or 200 mEq sodium and 100 mEq potassium for
at least 5 days before study. Balance was assessed by measurement of
sodium and potassium excretion in 24-hour urine collections. Each
subject received a detailed inpatient evaluation including a careful
history, physical examination, and an extensive laboratory
investigation, which involved a complete blood count and measurement of
serum creatinine, urea nitrogen, electrolytes, uric acid,
calcium, phosphate, alkaline phosphatase, lactic dehydrogenase, fasting
and 2-hour postprandial glucose, proteins with electrophoresis,
cholesterol, and triglyceride concentrations.
Complete urinalysis and quantitative urine cultures were performed at
least twice. Serial 24-hour urine collections were analyzed for
creatinine clearance and sodium, potassium, and protein
excretion. Each subject also had a chest x-ray, ECG,
intravenous pyelogram, and renal arteriogram. Blood
pressure was measured four times daily with subjects in both the
recumbent and standing positions.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Baseline systolic and diastolic blood
pressures and levels of serum creatinine, fasting blood
sugar, and 24-hour urine sodium were not significantly different in
obese subjects compared with those in age- and gender-matched lean
controls on either the low or high salt diet (Tables 1
and 2).
View this table:
[in a new window]
Table 1. Baseline Characteristics of Obese and Lean
Individuals on Low Salt Diet
View this table:
[in a new window]
Table 2. Baseline Characteristics of Obese and Lean
Individuals on High Salt Diet ). The 6
overweight subjects, reflected in a borderline high BMI between 25 and
26.9, had a somewhat higher RBF than did the lean controls, but this
was not significant (P=0.6). Those with frank obesity (BMI
between 27 and 35) had significantly higher RBF than controls
(P=0.013, n=13). The 5 subjects in whom renal perfusion
exceeded the 95% confidence interval were all 31 years of
age or younger, significantly younger than the obese group
(P<0.01). With high salt intake, however, renal perfusion
was not significantly different in 24 obese subjects (323±13 mL
· 100 g-1 ·
min-1) compared with lean controls (341±10
mL · 100 g-1 ·
min-1) (Figure 2).
View larger version (17K):
[in a new window]
Figure 1. Relation between age and RBF with low salt intake
in 21 obese subjects (circles) and in 95 lean kidney donors
(represented by the line of best fit with 95% confidence
interval). Data for the lean group have been published
previously.11
View larger version (18K):
[in a new window]
Figure 2. Relation between age and RBF) with high salt
intake in 24 obese subjects (circles) and in 52 lean kidney donors
(represented by the line of best fit with 95% confidence
interval). Data for the lean group have been published
previously.11 ).
View this table:
[in a new window]
Table 3. Baseline PRA Levels in Obese and Lean
Subjects
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Our goal was to determine how perfusion per unit of renal tissue
mass is influenced by sustained obesity in humans. We found renal
vasodilation resulting in increased perfusion per unit of renal tissue
mass in obese humans on low salt intake, but not when studies were
performed in subjects on high salt intake. These results did not
reflect differences in the degree of obesity in the low and high salt
groups. The difference in body weight between obese and lean averaged
21.6 kg with the low salt diet and 24.1 kg with the high salt diet.
Sodium intake was controlled because it is a major determinant of RBF,
at least in part by way of the RAS.11 The
specific salt intake–based difference in our results, however, was not
anticipated. This difference in the effect of salt intake can be
considered "hypothesis generating" and may provide insight into the
mechanism of obesity-associated renal vasodilation as discussed
below. 
the 85th
percentile for a population aged 20 to 29 years (BMI, 27.8 and 27.3 for
males and females, respectively); and "severely overweight" as a
BMI the 95th percentile (BMI, 31.3 and 32.3,
respectively).17 These criteria are lax.
Increased risk for CHD has been demonstrated in women with BMIs as low
as 2318 and is seen in the Framingham offspring
population in men and women with BMIs over
24.5.19 In this study we used a BMI of 25 as the
boundary in accordance with the 1985 US weight guidelines, which
defined a desirable BMI range between 19 and
24.13 The Canadian Expert Group on Weight
Standards were also in accordance.14 
). If we assume that the younger
subjects had been overweight for a shorter period of time, then it
follows that they were less insulin resistant and therefore
more susceptible to the vasodilatory effects of insulin. An alternative
explanation for this apparent age effect could be that very long-term
and sustained obesity eventually leads to a decline in renal
function—a possibility of some importance given the contribution of
obesity to hypertension and to diabetes mellitus.
Selected Abbreviations and Acronyms
AGT
=
angiotensinogen
Ang
=
angiotensin
BMI
=
body mass index
NHANES
=
National Health and Nutrition Examination Surveys
PRA
=
plasma renin activity
RAS
=
renin-angiotensin system
RBF
=
renal blood flow
Acknowledgments
This research was partially supported by National Institutes of
Health grants T32 HL-07609, NCRR GCRC M01RR026376, P01AC000559916, and
1P50 ML53000-01. We are grateful to Diana Capone for her assistance in
the preparation and submission of this manuscript.
Footnotes
Reprint requests to Norman K. Hollenberg, MD, PhD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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