Glomerular hemodynamics in severe obesity
Avry
Chagnac1,
Talia
Weinstein1,
Asher
Korzets1,
Edward
Ramadan2,
Judith
Hirsch1, and
Uzi
Gafter1
1 Department of Nephrology and
2 Department of Surgery A, Rabin Medical
Center-Golda (Hasharon) Campus, Petah Tikva 49372, Israel; and
3 Sackler School of Medicine, Tel Aviv
University, Tel Aviv 69978, Israel
 |
ABSTRACT |
Differential
solute clearances were used to characterize glomerular function in 12 nondiabetic subjects with severe obesity (body mass index >38). Nine
healthy subjects served as the control group. In the obese group,
glomerular filtration rate (GFR) and renal plasma flow (RPF) exceeded
the control value by 51 and 31%, respectively. Consequently,
filtration fraction increased. The augmented RPF suggested a state of
renal vasodilatation involving, mainly or solely, the afferent
arteriole. Albumin excretion rate and fractional albumin clearance
increased by 89 and 78%, respectively. Oral glucose tolerance tests
were suggestive of insulin resistance. Insulin resistance was
positively correlated with GFR (r = 0.88, P < 0.001)
and RPF (r = 0.72, P < 0.001). Mean arterial pressure was higher than in the control group. Fractional clearances of dextrans
of broad size distribution tended to be lowered. The determinants of
the GFR were estimated qualitatively by using a theoretical model of
dextran transport through a heteroporous membrane. This analysis
suggests that the high GFR in very obese subjects may be the result of
an increase in transcapillary hydraulic pressure difference (
P). An
abnormal transmission of increased arterial pressure to the glomerular
capillaries through a dilated afferent arteriole could account for the
augmentation in
P.
dextran; glomerular barrier; hyperfiltration; insulin resistance; transcapillary hydraulic pressure difference
 |
INTRODUCTION |
EXCESS BODY WEIGHT IS ASSOCIATED with functional and
structural renal changes, such as increased glomerular filtration rate (GFR), renal plasma flow (RPF) (3, 15, 24, 26), and urinary albumin
excretion (19, 26, 30). Experimental studies suggest that the kidney
could be involved in the pathogenesis of the increase in blood pressure
frequently affecting obese individuals (14, 27). Structural
abnormalities have been reported in obese animals (23) and obese humans
(1, 18, 22).
The kidney in nondiabetic obese patients exhibits glomerular
hyperfiltration that is not associated with glomerular disease or
nephrectomy. It thus provides an opportunity to study
glomerular hyperfiltration and its determinants. Two of these
determinants, the transcapillary hydraulic pressure difference (
P)
and the ultrafiltration coefficient (Kf), cannot be
directly measured in humans. Recently, single-nephron
Kf has been estimated by using a method that
combines morphometric measurements and a mathematical ultrastructural
model (11, 12). However, this approach requires the performance of
kidney biopsies, which is ethically questionable in patients without
kidney disease. In the absence of ultrastructural information, we have
determined sieving coefficients of dextrans of broad size distribution
in an effort to indirectly determine whether obesity leads to
hyperfiltration by elevating either
P or Kf. Our
findings are the basis of this report.
 |
METHODS |
Study population.
Twenty-one volunteers, 15 women and 6 men, aged 23-46 yr,
participated in the study. Twelve were patients with severe obesity [body mass index (BMI) >38], and nine were nonobese,
healthy people, who served as a control group. All denied a history of
renal disease; none had diabetes as defined by the criteria of the 1997 expert committee on the diagnosis of diabetes mellitus (25). None was treated for hypertension. All were found to have a normal serum creatinine level and a negative dipstick test for urinary protein. Table 1 shows the
characteristics of the two groups. Age and gender distribution were
similar in the two groups. The body weight and BMI of the obese group
were almost twice those of the control group. Their BMI varied between
38.1 and 49.7, with 11 of the 12 patients having morbid obesity, as
defined by a BMI above 40. Although within the normal range, the mean
fasting blood glucose in the obese group was higher than in the control
group. Fasting insulin was elevated more than twofold in the obese
group.
Informed consent was obtained from all participants. The study was
approved by the local Ethics Committee.
Study protocol.
Patients underwent an oral glucose tolerance test (OGTT). The OGTT was
performed at 8 AM after a 10-h fast. The subjects ingested 75 g of
glucose dissolved in water. Blood samples were withdrawn through an
indwelling intravenous catheter 10 and 1 min before and 60 and 120 min
after the ingestion for measurement of plasma glucose and insulin. In
one patient of the control group, fasting plasma glucose was measured
but OGTT was not performed. Four to 5 days later all subjects underwent
renal function tests. Each subject was studied at 8 AM after a light
breakfast low in protein content. The subjects were kept recumbent in a
hospital bed, and intravenous catheters were placed in each upper limb
for infusion of clearance markers and blood sampling. A priming dose of
inulin (50 mg/kg), p-aminohippuric acid (PAH; 8 mg/kg), and
dextran 40 (130 mg/kg) was administered. Thereafter, inulin, PAH, and
dextran 40 were infused continuously. A water load (15 ml/kg) was given during the first 60-min prime, so as to promote a high rate of urine
flow. Four accurately timed urine collections were then obtained by
spontaneous voiding. Peripheral venous blood was drawn to bracket each
urine collection. Blood pressure was measured during each urine collection.
GFR was determined from the average inulin clearance. RPF was
calculated by dividing the average PAH clearance by an assumed renal
PAH extraction ratio of 0.9. Oncotic pressure (
) was calculated by
using the equation (5)
= 1.645 TP + 0.29 (TP)2, where
TP is the total serum protein concentration. Fractional clearances of
dextran macromolecules (
D) were calculated by using the
equation
D = (U/P)D/(U/P)In,
where (U/P)D and (U/P)In are urine-to-midpoint
plasma concentration ratio of dextran and inulin, respectively. Mean
arterial pressure was calculated as diastolic pressure plus one-third
of the pulse pressure. BMI was calculated as: BMI = BW/H2,
where BW is body weight (in kg) and H is height (in m).
Laboratory procedures.
Plasma and urinary concentrations of inulin and PAH were analyzed by
colorimetric methods (4, 28). Plasma glucose and serum albumin and
total protein concentrations were measured by using standard laboratory
methods. Serum insulin was measured by using a radioimmunoassay
(Sorin-Biomedica, Saluggia, Italy). Urine albumin was measured by
nephelometric methods (Beckman, Galway, Ireland). Separation of dextran
40 in protein-free filtrates of plasma and urine into narrow fractions
was achieved by high-performance liquid chromatography using two
columns in series (Ultrahydrogel 250 and 500; Waters Division,
Millipore, Milford, MA) (21). The columns were calibrated with three
narrowly dispersed dextran fractions of known molecular weight (MW;
9.9, 25.6, 53.5,and 72.6, respectively). Dextran
concentration was measured by using a refractive index detector (no.
RID-6A, Instrumentation Shimadzu). An integrator (no. 4270, Spectraphysics, San Jose, CA) was used to divide the chromatogram into
four slices per minute during the 40-min run. The integrated area of
each slice was equated with the dextran concentration at the
corresponding retention time. MW was calculated from its linear
relationship with retention time, and molecular radius
(rs) was calculated by using the equation
rs = 0.33 × (MW)0.463. The
urine-to-plasma concentration ratio was calculated for each dextran
fraction at 2-Å intervals over a molecular radius range of
34-58 Å.(20).
Analysis of glomerular membrane-pore structure.
To characterize the size-selective properties of the glomerular barrier
in each group of subjects, we employed two theoretical models, each of
which represents the glomerular capillary wall as a heteroporous
membrane characterized by two pore parameters (8). According to the
first of these models (isoporous model with shunt), the major portion
of the capillary wall is assumed to be perforated by restrictive,
cylindrical pores of identical radius (r0). The
model assumes that there exists in addition a parallel "shunt
pathway" that does not discriminate among the infused dextrans on
the basis of size, and through which passes a small fraction of the
filtrate volume. The shunt pathway is characterized by a parameter,
0, that governs the fraction of filtrate volume passing
through the nonrestrictive portion of the membrane. The second model
represents the glomerular capillary wall as being perforated by
cylindrical pores with a continuous log-normal distribution of pore
radii (log-normal model). The two parameters, which characterize this
latter representation, are the mean pore radius (U) and the
standard deviation about the mean (S) of the log-normal
distribution of pore sizes. Each model also estimates volume flows and
fluxes and protein concentration along the length of glomerular
capillaries, thereby permitting computation of the ultrafiltration
coefficient Kf, which is the product of effective
hydraulic permeability and total glomerular capillary surface area in
the two human kidneys. These models take into account the effect of GFR
determinants on convective and diffusive transmembrane transport,
requiring knowledge of GFR, RPF, afferent arteriole oncotic pressure,
and
P (6, 9). Because
P cannot be measured directly in humans, a
sensitivity analysis was performed by using the mean group data.
P
values of 35, 40, and 45 mmHg were assigned. Individual data were then analyzed in 5 control and 11 obese subjects by using the
P value, providing the least
2 in the sensitivity analysis.
Statistical analysis.
Normally distributed data are expressed as means ± SE. Variables with
skewed distribution, such as albumin urinary excretion rate and
fractional albumin clearance, are expressed as median (range). The
significance of differences between the obese and control groups was
evaluated by a two-tailed Student's t-test. Student's
t-test was applied to nonnormally distributed data after log
transformation. Pearson correlation coefficients were used to evaluate
correlations between variables.
 |
RESULTS |
Oral glucose tolerance test.
Table 2 summarizes the results of the oral
glucose tolerance test. The area under the glucose and insulin curves
after oral glucose load was increased in the obese group by 67 and
230%, respectively. The ratio of the insulin-to-glucose area under the curves of the obese group was twice as high as that of the control group (0.79 ± 0.08 vs 0.40 ± 0.04, respectively, P < 0.005). These data are consistent with marked insulin resistance.
Filtration dynamics.
Filtration dynamics data are shown in Table
3. GFR was 51% higher in the obese than in
the control group. It was elevated in 8 of the 12 patients. The
distribution of GFR in the two groups is depicted as a histogram in
Fig. 1. An increase in RPF was
proportionally smaller, averaging 31%. The increase in GFR was thus
associated with an increase in filtration fraction. Mean arterial
pressure, although normal in both groups, was higher in the obese
group. Plasma oncotic pressure, the force opposing the formation of
filtrate, was identical in the two groups.

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Fig. 1.
Distribution of glomerular filtration rate (GFR) in control group (dark
gray bars) and obese group (filled bars). n, No. of subjects.
|
|
A positive correlation was found between GFR and RPF in the combined
obese and normal groups (r = 0.86, P < 0.001),
suggesting that the change in RPF accounted for 74% of the variation
in GFR. The area under the insulin curve was correlated with both RPF (r = 0.72, P < 0.001) and GFR (r = 0.88, P < 0.001).
Renal macromolecule handling.
Albumin excretion rate was increased in the obese group: 8.5 (4.4-152) and 4.5 (2.5-7.0) µg/min in the obese and normal
groups, respectively (P < 0.005). The fractional clearance of
albumin was 0.16 (0.1-2.3) × 10
5 and 0.09 (0.07-0.18) × 10
5 in the obese and control groups,
respectively (P < 0.05).
The mean dextran-sieving profiles in the obese and control groups are
compared in Fig. 2. Fractional
dextran-sieving clearances were nonsignificantly decreased in the obese
group.

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Fig. 2.
Dextran-sieving coefficients in control group ( , dotted line) and
obese group ( , solid line). Bars, 1 SE for each sieving coefficient.
Sieving coefficients of 2 groups are not significantly different.
n, No. of subjects.
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|
Analysis of membrane parameters.
Heteroporous membrane models were used to estimate membrane parameters
for the control and obese groups from the mean dextran-sieving curves
profiles illustrated in Fig. 2. These models take into account the
effect of GFR determinants on convective and diffusive transmembrane
transport, requiring knowledge of GFR, RPF, afferent arteriole oncotic
pressure, and
P (7, 8). Because
P cannot be directly measured in
humans, we performed a sensitivity analysis, assigning
P values of
35, 40, and 45 mmHg. We then subjected the data to two theoretical
models, the isoporous+shunt model and the log-normal model. The sieving
profiles predicted by each model are illustrated in Fig.
3A for the control group and in Fig. 3B for the obese group. Inspection of each panel of Fig. 3
suggests that the log-normal model replicates the observed findings better than the isoporous+shunt model. This is confirmed by a lower sum
of at least
2 in the former, indicating that, for any
level of
P, the log-normal model predicts the observed sieving curve
better than does the isoporous+shunt model. Thus the former model was
used to estimate
P. Findings are summarized in Table
4. Whereas the best fit
P value for the
control sieving curve is 35 mmHg, the corresponding best fit in the
obese group is 40 mmHg. We next analyzed the intrinsic membrane
properties of the individuals by using the aforementioned best fit
P
values, i.e., 35 and 40 mmHg for the control and obese subjects,
respectively (Table 5). This analysis
indicates that the control and obese groups have essentially similar
values for Kf (14.0 vs. 16.5 ml · min
1 · mmHg
1,
respectively), mean pore radius (45.3 vs. 46.9 Å,
respectively), and breadth of the pore size distribution (1.19 and
1.18, respectively).


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Fig. 3.
A: relationship between predicted and observed sieving
coefficients. Predictions for isoporous+shunt model (solid curve) and
log-normal model (dotted line) are compared with observed mean sieving
coefficients ( ). Transcapillary hydraulic pressure difference.
B: relationship between predicted and observed sieving
coefficients. Predictions for the isoporous+shunt model (solid curve)
and log-normal model (dotted line) are compared with observed mean
sieving coefficients ( ).
|
|
 |
DISCUSSION |
This study shows that both GFR and RPF of extremely obese patients are
increased, the GFR being relatively more elevated than the RPF,
resulting in an increased filtration fraction. The augmented RPF
suggests a state of renal vasodilatation involving, mainly or solely,
the afferent arteriole. RPF is a determinant of GFR independently of
the capillary hydrostatic pressure: its increase is predicted to lower
the intraluminal concentration of macromolecules as blood flows axially
along the glomerular capillaries (9). This results in a decrease in
glomerular intracapillary oncotic pressure, thus enhancing the net
ultrafiltration pressure and contributing to the elevated GFR. However,
because the increase in filtration fraction offsets the effect of the
increase in RPF on the glomerular oncotic pressure, factors other than
oncotic pressure must have contributed to the elevation of GFR.
Although within the normal range, the MAP was higher in the obese group than in the control group. The combination of increased arterial pressure abnormally transmitted to the glomerular capillaries through a
dilated afferent arteriole is expected to cause an elevated glomerular
capillary pressure, resulting in an increased transcapillary pressure
gradient
P and an elevated GFR. In the consideration of this, the
third factor determining GFR, Kf, could be, on
theoretical grounds, either normal, decreased, or increased. Because
neither
P nor Kf is directly measurable in
humans, we have attempted to detect changes in the direction of each
quantity by analyzing the sieving data with heteroporous models of
glomerular size selectivity (8).
The low-radius end of the sieving curve tended to be depressed.
However, this difference did not reach significance. Theoretical and
experimental studies on the effects of glomerular hemodynamics on
sieving coefficients of macromolecules (6) have shown that increased
P and RPF and depressed Kf are predicted to
depress the small dextran-sieving coefficients. Thus the nonsignificant change in the sieving coefficients could be the end result of the
effects of opposing forces, elevated
P and RPF, tending to depress
the sieving coefficients, and an increased Kf,
partially offsetting this effect. Yet the sieving curve findings should be interpreted cautiously. Edwards and Deen (13) have analyzed the
limitations of the method by using sieving data to estimate glomerular
pressure. They have defined two kinds of errors responsible for the
inconsistent results obtained by this method: random experimental errors and systematic errors due to imperfections in the theoretical models used to analyze the data. The authors have shown that these errors make a reliable quantitative estimation of
P from the sieving
data unlikely. Furthermore, the shape of dextran molecules alters
during transglomerular permeation. As a result, their transport is
enhanced and the analysis of the sieving data of these molecules leads
to an overestimation of the glomerular pore size. This overestimation affects the evaluation of the fraction of filtrate volume passing through the nonrestrictive portion of the membrane, but not that of
Kf (2). Thus this drawback of dextran is of limited
consequence in the present study. In the consideration of the
limitations of this method, the estimate of
P obtained by using a
model of transport through a heteroporous membrane should be regarded
as qualitative. The group mean data were analyzed by using two models of glomerular filtration, the log-normal and the isoporous+shunt models. From the least square analysis, the best fit was obtained by
the log-normal model. It predicted a higher
P and a similar Kf in the obese, compared with the control group.
The present findings are at variance with another model of
hyperfiltration, the diabetic kidney at an early stage, studied in Pima
Indians with non-insulin-dependent diabetes mellitus of <3-yr
duration (21). Differential solute clearance tests revealed a
significant elevation of the sieving coefficients. The hyperfiltration
of this obese population with early diabetes was not associated with a
significantly elevated RPF, in contrast to the nondiabetic obese population studied in the present report. Because an increase in RPF is
expected to depress the small dextran-sieving coefficients, RPF did not
constitute a force depressing the sieving curve, leaving unbalanced the
eventual influence of an increased Kf toward
elevation of the sieving cefficients. In fact, by modeling at different
P values, Myers et al. (21) showed that at any given
P value, Kf was increased. Thus the two models of
hyperfiltration, the obese nondiabetic subjects and the obese patients
with early NIDDM, appear to differ as far as glomerular hemodynamics is concerned.
The filtration fraction value of the control group in the present study
is relatively low compared with that reported in previous studies,
raising the concern of a possible bias in the interpretation of the
abnormalities found in the obese. However, this difference is in large
part artificial and reflects mostly the method used to estimate RPF.
Most studies equate RPF with PAH clearance, not taking into
consideration the incomplete extraction of PAH by tubules. In the
present study, an assumed extraction ratio of 0.9 was used, giving a
relatively high RPF and a relatively low filtration fraction. Because
this correcting factor has been applied to both control and obese
groups, it does not influence the results of the comparison between the
groups. In taking into consideration this mode of calculation, the
results for the control group of the present study fall well into the
normal range (data not shown).
We wish to emphasize that the GFR in the present study has not been
corrected for body surface area. Because the number of nephrons does
not increase with increasing body fat, increasing obesity must result
in an increase in the single-nephron GFR. Absolute GFR reflects this
phenomenon whereas correcting GFR for body surface area obscures it. We
have accordingly analyzed the data by using the uncorrected, absolute
GFR. Finally, it should be noted that despite the marked
hyperfiltration disclosed by the obese group, one-third of the subjects
in this group had a GFR in the normal range. A possible explanation is
that the GFR of these subjects was in the low-normal range before they
gained weight and that this normal GFR represents hyperfiltration.
Another possibility is that unknown factors may avert the hemodynamic changes in some obese subjects.
Obesity is associated with marked insulin resistance. The group of
obese patients studied here exhibited features suggestive of marked
insulin resistance, which was correlated with RPF, GFR, and filtration
fraction. Dengel et al. (10), studying a population of obese
nondiabetic patients with mild renal insufficiency, have shown a
negative correlation between glucose disposal rate during hyperinsulinemic euglycemic clamp and filtration fraction, i.e., a
positive correlation between insulin resistance and filtration fraction. This link could be an epiphenomenon indicative of an undetermined process occurring in the kidney of obese insulin-resistant patients and not directly caused by insulin resistance. However, experimental studies have suggested a direct effect of insulin on the
glomerular microcirculation. Juncos and Ito (17) have studied in vitro
isolated segments of rabbit glomerular arterioles and shown that
insulin reduces norepinephrine-induced efferent arteriolar
constriction, an effect that is predicted to lower
P. Insulin
resistance involving glomerular vessels would thus result in an
increased
P. Tucker et al. (29) and Hayashi et al. (16) have
confirmed the vasodilatory action of insulin on rat renal microvessels.
However, their studies failed to show a preferential effect on the
efferent arteriole, thus not supporting the concept of insulin
resistance as a cause of increased
P. Thus although the glomerular
hemodynamic alterations we have shown in the obese population could be
the consequence of resistance of the glomerular microcirculation to
insulin action, this issue is still unresolved.
In summary, the elevated GFR of very obese nondiabetic patients is
associated with an increased RPF. The analysis of dextran-sieving data
suggests, but does not prove that the pathogenesis of hyperfiltration differs from that of the diabetic kidney, in that it is mainly or
solely due to an increased
P. The role of insulin resistance as a
factor contributing to these glomerular hemodynamics changes remains to
be clarified.
 |
ACKNOWLEDGEMENTS |
We are grateful to Dr. Bryan D. Myers, Div. of Nephrology, Stanford
Univ. Medical Center, Stanford, CA, for giving us the opportunity to
use the facilities in his laboratory and to Kristina Blouch, Div. of
Nephrology, Stanford University Medical Center, for advice in the
measurement of dextran concentrations. We also thank Dr. Chaim
Chaimoff, Dept. of Surgery A, Rabin Medical Center-Golda Campus, for
help in recruiting patients.
 |
FOOTNOTES |
Plasma and urine dextran concentrations were measured during a
sabbatical leave at Stanford University.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: U. Gafter,
Nephrology Dept., Rabin Medical Center-Golda Campus, 7 Keren Kayemet
St. , Petah Tikva 49372, Israel (E-mail :
avryc{at}netvision.net.il).
Received 24 June 1999; accepted in final form 30 November 1999.
 |
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