ACE inhibition and ANG II receptor blockade improve glomerular
size-selectivity in IgA nephropathy
Andrea
Remuzzi1,
Norberto
Perico1,2,
Fabio
Sangalli1,
Giovanni
Vendramin3,
Monica
Moriggi3,
Piero
Ruggenenti1,2, and
Giuseppe
Remuzzi1,2
1 Department of Kidney
Research, Mario Negri Institute for Pharmacological Research, 24125 Bergamo; 2 Unit of Nephrology and
Dialysis, Ospedali Riuniti di Bergamo, Bergamo; and
3 Unit of Nephrology and Dialysis,
Ospedale Treviglio-Caravaggio, 24047 Treviglio, Italy
 |
ABSTRACT |
Protein
trafficking across the glomerular capillary has a pathogenic role in
subsequent renal damage. Despite evidence that angiotensin-converting
enzyme (ACE) inhibitors improve glomerular size-selectivity, whether
this effect is solely due to ANG II blocking or if other mediators also
play a contributory role is not clear yet. We studied 20 proteinuric
patients with IgA nephropathy, who received either enalapril (20 mg/day) or the ANG II receptor blocker irbesartan (100 mg/day) for 28 days in a randomized double-blind study. Measurements of
blood pressure, renal hemodynamics, and fractional clearance of neutral
dextran of graded sizes were performed before and after 28 days of
treatment. Both enalapril and irbesartan significantly reduced blood
pressure over baseline. This reduction reached the maximum effect
4-6 h after drug administration but did not last for the entire
24-h period. Despite transient antihypertensive effect, proteinuria was
effectively reduced by both treatments to comparable extents. Neither
enalapril nor irbesartan modified the sieving coefficients of small
dextran molecules, but both effectively reduced transglomerular passage
of large test macromolecules. Theoretical analysis of sieving
coefficients showed that neither drug affected significantly the mean
pore radius or the spread of the pore-size distribution, but both
importantly and comparably reduced the importance of a nonselective
shunt pathway. These data suggest that antagonism of ANG II is the key
mechanism by which ACE inhibitors exert their beneficial effect on
glomerular size-selective function and consequently on glomerular
filtration and urinary output of plasma proteins.
angiotensin II; angiotensin II receptor antagonism; dextran
fractional clearance; glomerular size-selectivity; immunoglobulin A; proteinuria
 |
INTRODUCTION |
ANIMALS AND HUMANS with proteinuric nephropathies,
either of diabetic or nondiabetic origin, tend to develop renal
structural damage associated with progressive renal function decline
over time. Studies of animals have disclosed that glomerular
adaptations to the loss of functioning renal mass, such as hypertrophy
and concomitant increase in glomerular capillary pressure and flow, are
common denominators of progressive nephropathies after an initial
insult has reduced the number of functioning nephrons (2, 12). Evidence
is also available from studies of experimental animals that protein
trafficking across the glomerular capillary has a pathogenetic role in
subsequent renal damage via the nephritogenic insult generated by the
process of tubular endocytosis of filtered proteins (5-7, 15, 42).
Moreover, an analysis of the most recent studies allows one to conclude
that proteinuria was a major determinant of the rate at which renal
function is lost in human renal diseases (10, 35, 44, 46). This body of
evidence suggests that glomerular hemodynamic and membrane permeability changes are related to each other to the extent that enhancing intraglomerular capillary pressure enlarges pore radii in
various models, including renal vein constriction (52) and immune
nephropathies (53).
That ANG II mediates glomerular permselective function via the opening
of large unselective pores after elevations in transmembrane pressure
differences is consistent with findings of enhanced fractional clearance of large dextran macromolecules in the isolated perfused kidney (27) and in animal models in vivo (9). Angiotensin-converting enzyme (ACE) inhibitors, via their unique property of reducing membrane
pore dimensions (40) thereby improving sieving function, are more
renoprotective than other drugs in animal models of renal disease
progression, from diabetic to immune or toxic models (1, 3, 55), and
limit decline of glomerular filtration rate (GFR) in human diabetic
(28) and nondiabetic (19, 29) renal diseases. The protective effect of
ACE inhibitors appears, however, confined to patients with high values
of urinary proteins (i.e., >2-3 g/24 h) in most trials (19, 29).
Furthermore, some studies have found that ACE inhibitors, and possibly
other antihypertensives, limit subsequent renal function decline to the
extent that they lower proteinuria (8, 25). Despite this experimental
and human evidence that ACE inhibitors improve glomerular
size-selectivity via their properties of interfering with the
renin-angiotensin axis, whether the protective effects of the above
class of compounds is solely due to ANG II blocking or if other
mediators or hormonal systems may also play a contributory role is
still far from clear. ACE inhibitors do block a number of
other systems, including the bradykinin system, that are implicated in
renal damage (22-24, 49). Specifically, an ACE inhibitor, but not
an ANG II receptor antagonist, reduced proteinuria in early
aminonucleoside nephrosis, an effect that was not observed when a
bradykinin antagonist was simultaneously administered (50). Moreover,
infusion of ANG II failed to reverse lisonopril's effect of improving
size-selective function in patients with nondiabetic chronic renal
disease (21). The availability of receptor antagonists that effectively
and selectively prevent ANG II binding to
AT1-type receptors without altering other hormonal systems provides an opportunity to test in
humans whether inhibition of the local action of ANG II reversed size-selective dysfunction and acutely reduced proteinuria, a valuable
predictor of long-term protection toward declining GFR (44, 45). We
recently had the opportunity to study a group of patients with IgA
nephropathy, who were randomized to receive enalapril or irbesartan for
28 days in a double-blind study of two parallel groups (33). This was a
sequential multidrug study mainly designed to address whether an
additional drug (in this case indomethacin) added after either
treatment could further reduce proteinuria. In this group of patients,
sequential measures of blood pressure and evaluation of renal
hemodynamics and glomerular sieving function combined with theoretical
analysis of fractional clearance of test macromolecules before and
after either drug allowed us to compare the antihypertensive effect
with glomerular hemodynamics and intrinsic glomerular membrane
permeability properties to macromolecules. The results of these studies
form the basis of this report.
 |
METHODS |
Patient population. Twenty patients,
16 males and 4 females aged 20-65 yr with biopsy-proven IgA
mesangial nephropathy, were enrolled into the study. The
patients were recruited from the outpatient clinic of the Unit of
Nephrology of Ospedali Riuniti (Bergamo, Italy) and Ospedale
Treviglio-Caravaggio (Treviglio, Italy). Patients were persistently
proteinuric (0.5-4.0 g urinary proteins/24 h) with normal or
moderately reduced renal function (serum creatinine 0.9-2.4
mg/dl). No previous or concomitant immunosuppressive treatments and no
nonsteroidal anti-inflammatory drugs were used in the 3 mo before
enrollment. Informed consent from each patient was obtained before
entry into the study. Twelve patients were normotensive, and the
remaining patients were on conventional antihypertensive treatments.
Antihypertensive treatment was stopped before the selection visit was
performed. Patients were randomized to receive the ACE inhibitor
enalapril (20 mg/day; Sanofi Winthrop, Gentilly Cedex, France) or the
ANG II receptor antagonist irbesartan (100 mg/day; Sanofi Winthrop) in
a double-blind study with two parallel groups. The irbesartan dose was
chosen according to a previous dose-finding study of lowering blood
pressure in patients with essential hypertension.
Study protocol. After enrollment in
the study, a 4-wk single-blind placebo washout period from previous
treatments was performed (33). One week before the end of this washout
period, patients underwent 24-h protein excretion measurements and a
renal clearance study (baseline) to evaluate GFR, renal plasma flow
(RPF), and fractional clearance of albumin. At the end of the placebo
phase, patients were randomized to enalapril or irbesartan and
continued the assigned treatment for the following 28 days, after which urinary protein excretion was measured and a second clearance study was
performed with the same modality of baseline evaluation.
Clearance studies. Inulin and
para-aminohippuric acid (PAH) clearance were measured under a
steady state of water diuresis induced by oral water loading as
previously described (33, 39). Briefly, primed infusion of inulin and
PAH was followed by slow intravenous administration of neutral dextran
test macromolecules (130 mg/kg, Dextran-40, Rheomacrodex; Pharmacia,
Uppsala, Sweden) after ~15 min. A sustained infusion of inulin and
PAH was then started to maintain constant plasma concentrations of both
tracers. Drug or placebo was administered 30 min after the start of the priming infusion of inulin and PAH. After an equilibration period of
~60 min, a timed urine collection of ~30 min was made by
spontaneous voiding for evaluation of dextran fractional clearance.
Subsequently, six clearance periods of 2 h each were
performed to monitor eventual changes in renal hemodynamics and albumin
fractional clearance acutely induced by single drug administration.
Blood samples were collected at the beginning and end of each clearance
period. Blood pressure was measured every 2 h during the entire
clearance study. Urine and plasma samples obtained during the first
clearance period were used to determine fractional clearance of dextran
molecules. In the same urine and plasma samples, albumin concentration
was also measured.
Inulin and PAH concentrations in plasma and urine samples were
determined with colorimetric assays as previously described (39).
Separation of graded-size dextran molecules and inulin in plasma and
urine samples was performed by gel permeation chromatography on a
Sephacryl S-300 column (1.6 × 95 cm) using dextran standards of
known molecular weight (Pharmacosmos, Viby Sj., Denmark) for column
calibration. Molecular radii of individual dextran fractions were
calculated according to Oliver et al. (32). Dextran concentrations in
eluted fractions were determined using the anthrone reaction as
previously described (39, 41, 48). Fractional clearance of dextran
molecules was computed as
where
(U/P)D and
(U/P)IN are the urine-to-plasma
concentration ratios of dextran and inulin, respectively. Total protein concentration in plasma samples collected during the first clearance period and in urine samples collected over the 24-h period were measured by an automatic analyzer (Synchron CX5; Beckman, Furlenton, CA). Albumin concentration in plasma and urine samples collected during
the clearance studies was determined by nephelometric technique (Beckman; detection limit of assay is 2 µg/ml of albumin in urine samples). GFR and RPF were calculated as inulin and PAH clearance, respectively, and normalized for body surface area. To take into account that extraction of PAH during renal passage is not complete in
these patients (4), we assumed a renal extraction coefficient of 0.8 and 0.7, respectively, for patients with GFR higher or lower than 80 ml · min
1 · 1.73 m
2.
Theoretical analysis of glomerular membrane
transport. We investigated intrinsic glomerular
membrane permeability properties of macromolecules using the
mathematical model of glomerular size-selectivity described in detail
previously (13, 36, 41). This model simulates glomerular filtration of
neutral test macromolecules on the basis of assumed membrane
permeability properties and measured determinants of glomerular
ultrafiltration. The model assumes that the glomerular membrane is
perforated by cylindrical pores having a bimodal distribution of their
radii. The radius of restrictive membrane pores is assumed to have a
lognormal probability distribution. In parallel with selective pores, a
shunt pathway consisting of large pores that do not restrict the
passage of large test macromolecules is also assumed (13, 41). This
distribution of pore radii is therefore characterized by three
adjustable parameters: u, s, and
0. The parameters
u and
s represent, respectively, the mean
and the standard deviation of the corresponding normal probability distribution, and
0 represents
the fraction of ultrafiltrate that would pass through the shunt if
plasma protein were absent (13, 41). The model is based on another
freely adjustable parameter, the ultrafiltration coefficient
(Kf, the product
of hydraulic permeability and filtering surface area of the glomerular membrane). We calculated
Kf (extended to
the entire glomerular population in both kidneys) using an established
model of glomerular ultrafiltration (14). The intrinsic membrane
permeability parameters were calculated as shown previously (39, 41),
and the sum of squared errors between experimental and calculated
sieving coefficients was minimized at single patient level during each clearance study.
Statistical analysis. Data are
expressed as means ± SD or median and range, as specified. Results
were analyzed using two-way ANOVA, and specific comparisons among
different groups were performed by two-tailed Student's
t-test using the Bonferroni correction (51). Values of urinary protein excretion and albumin fractional clearance were log-transformed before statistical analysis. Statistical analysis was performed using the software package StatView (Abacous Concepts, Berkeley, CA).
 |
RESULTS |
Blood pressure and kidney function.
The effects of 4-wk treatment with enalapril or irbesartan on systemic
and renal hemodynamic parameters are summarized in Table
1. Values of renal hemodynamic parameters
and albumin fractional clearance are the average of the six clearance
periods. The randomization process generated two groups: 11 patients in
the enalapril group, 9 in the irbesartan group. The two groups were
statistically different for blood pressure, urinary protein excretion,
and albumin fractional clearance at baseline. In patients treated with
enalapril, blood pressure and urinary proteins were lower than in
irbesartan-treated patients. For this reason, comparisons of the
effects of the two drugs were performed considering the relative
changes induced by individual treatments as well as by direct
comparison of absolute values of end-point parameters before and after
treatment (see Table 1).
As shown in Table 1, blood pressure did not change significantly during
the time course of baseline (placebo) evaluation but was effectively
reduced during the clearance study performed at the end of the
treatment period. The maximum antihypertensive effect was observed
4-6 h after drug administration. At this time, mean blood pressure
was slightly but significantly lower at the end of enalapril or
irbesartan treatment than at baseline evaluation. By contrast, trough
levels of blood pressure (measured before drug administration) were
only numerically reduced for both treatments; mean blood pressure (in
mmHg) averaged 101 ± 9 vs. 96 ± 9 for baseline vs. enalapril,
and 112 ± 8 vs. 110 ± 7 mmHg for baseline vs. irbesartan. These
differences did not reach statistical significance.
The mean GFR values of the six clearance periods were not affected
significantly by 28 days of enalapril treatment (see Table 1).
Similarly, mean values of RPF at the end of the treatment period were
only numerically higher than at baseline; the differences did not reach
statistical significance. In patients given irbesartan, the mean values
of GFR were comparable at baseline evaluation and after treatment. By
contrast, mean RPF was significantly elevated by drug treatment. As a
result, mean filtration fraction remained constant in enalapril-treated
patients, whereas it decreased significantly at day
28 of treatment in those given irbesartan. Urinary
excretion rate of total proteins and albumin as well as albumin
fractional clearance decreased significantly with enalapril treatment
(see Table 1). Irbesartan treatment significantly reduced urinary excretion of total proteins and albumin but, unlike enalapril, only
numerically lowered albumin fractional clearance.
The dynamics of mean blood pressure changes induced by enalapril and
irbesartan during the second clearance study is reported in Fig.
1. In enalapril-treated patients, mean
blood pressure was significantly reduced during the clearance study
4-10 h after drug administration compared with values measured
before drug administration; then blood pressure returned to
preadministration level. These changes in blood pressure were not
associated with glomerular hemodynamic changes such as RPF, nor with
acute changes in albumin fractional clearance during the course of the
12-h observation period. Similarly, in irbesartan-treated patients, mean blood pressure transiently and significantly decreased with time at 4 and 6 h after drug administration compared with values measured before administration; then blood pressure returned to preadministration values. Also in this patient group, acute change in
blood pressure was not associated with significant changes in RPF and
albumin fractional clearance. Thus the adopted doses of the two
treatments acutely and transiently reduced mean blood pressure but did
not induce acute changes in glomerular plasma flow rate and urinary
albumin excretion.

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Fig. 1.
Time course of effect of single-dose administration of enalapril and
irbesartan on mean blood pressure (BP), renal plasma flow (RPF) and
albumin fractional clearance ( albumin) at end of treatment period.
Arrows indicate time of drug administration.
* P < 0.05 vs.
preadministration in same group.
** P < 0.01 vs.
preadministration in same group.
|
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Neutral dextran fractional clearance.
Sieving coefficients of neutral dextran molecules of graded sizes
(26-66 Å) measured in basal condition and at the end of
enalapril or irbesartan treatment are reported in Table
2 and Fig.
2. Fractional clearance of small dextran
molecules (radii < 42 Å) was not significantly affected by
enalapril treatment. Sieving coefficients of larger dextran molecules
(radii 42-44 and 64-66 Å) were significantly lower after enalapril treatment than at baseline. Similarly, irbesartan administration had no effect on fractional clearance of small dextrans
(radii < 38 Å) but significantly reduced the sieving coefficient of molecules of larger size (38-50 and 54-66
Å).

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Fig. 2.
Fractional clearance of neutral dextran macromolecules as a function of
effective molecular radius measured at baseline and end of treatment
period. * P < 0.05 vs. end of
treatment in same group. ** P < 0.01 vs. end of treatment in same group.
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Dextran sieving coefficients and renal hemodynamic parameters measured
during the first clearance period were used as input data for the
theoretical analysis of glomerular size-selective function. This
theoretical approach requires the assumption of glomerular
transmembrane hydraulic pressure difference (
P) that cannot be
directly measured in humans. In keeping with previous studies (31, 39),
we assumed that
P = 45 mmHg in these patients at baseline
conditions, a value slightly elevated above what is believed to be a
normal value (40 mmHg) to take into consideration the moderate
hypertension that characterizes our patient population. Because in
experimental models of glomerular disease ACE inhibitors and ANG II
receptor blockers have been shown to selectively decrease glomerular
capillary pressure (26, 30), we assumed a value of
P = 40 mmHg for
theoretical analysis of sieving coefficients measured at the end of the
treatment period. In addition, because of the uncertainty in estimating
representative values of
P, we also considered the possibility that
despite antihypertensive treatments, glomerular capillary pressure was
unchanged, and we performed theoretical analysis of sieving
coefficients at the end of the treatment period assuming
P = 45 mmHg.
The results of the theoretical analysis are reported in Table
3 and in Fig.
3. Calculated values of
Kf were
significantly higher after enalapril and irbesartan treatment compared
with baseline, but this effect was related to the assumption of a lower
P value (40 mmHg). With the assumption of
P = 45 mmHg,
Kf was comparable
at baseline and at end-of-treatment evaluation. The effects of the
assumed
P values (40 vs. 45 mmHg) were less important for the other
calculated membrane pore-size parameters. The same statistically
significant changes in these parameters between baseline and
end-of-treatment evaluation were computed assuming either that
P was
reduced or that it remained constant (see Table 3). This is in keeping
with previous observations that assumed values of
P do not
importantly affect calculated membrane pore-size parameters (13, 41).
Mean pore radius of the pore-size distribution u was reduced to a significant extent
by enalapril treatment compared with baseline values. By contrast, the
spreading of the pore-distribution s
significantly increased at the end of 28-day enalapril treatment. In
irbesartan-treated patients, mean pore radius
u was reduced and the spreading of
distribution s increased. These,
however, were only numerical changes that did not attain statistical
significance. In Fig. 3 we graphically represented the effect of the
two treatments on the pore-size distribution function
g(r) previously described (41).
Values of g(r) as a function of pore
radius were calculated using mean values of
u and
s reported in Table 3 (assuming
P = 40 mmHg at the end of both treatment periods). Enalapril and irbesartan
similarly reduced the radius of the restrictive membrane pore
population. We also calculated the membrane pore parameter
0, which describes the relative
importance of the shunt pathway and represents the filtration volume
fraction that would pass through the shunt if plasma proteins were
absent. An important effect of enalapril treatment was observed in
calculated values of the shunt parameter
0. On average,
0 was reduced by more than 55 and 40% by enalapril treatment for
P = 40 and 45 mmHg, respectively, compared with basal evaluation (Table 3). Similarly, irbesartan reduced the
0 by
more than 49 and 43% for
P = 40 and 45 mmHg, respectively, compared
with baseline. As shown in Fig. 4,
individual changes in shunt parameter at the end of enalapril or
irbesartan treatment paralleled those of 24-h urinary protein excretion
rate.

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Fig. 3.
Probability distribution of membrane pore sizes
[g(r)] and relative
contribution of shunt pathway
( 0) calculated at baseline
and at end of treatment period (assuming P = 40 mmHg).
* P < 0.05 vs.
baseline in same group.
** P < 0.01 vs.
baseline in same group.
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Fig. 4.
Changes in urinary protein excretion and in shunt parameter values
associated with drug treatment at individual patient level.
* P < 0.05 vs. baseline in
same group. ** P < 0.01 vs.
baseline in same group.
|
|
Data collected during the study also allowed us to compare the
antihypertensive effect observed during the treatment period with the
corresponding reductions in urinary proteins and glomerular size-selective parameters at the level of individual patients, independently from the treatment used to obtain different degrees of
blood pressure reduction. As represented in Fig.
5, percent changes in urinary protein
excretion induced by the 28-day treatment with either enalapril or
irbesartan did not correlate with corresponding changes in mean blood
pressure over the same treatment period. This same situation was
observed comparing calculated changes in the shunt parameter
0 (for
P = 40 mmHg) and
corresponding changes in mean blood pressure during the treatment
period.

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Fig. 5.
Percent changes in urinary protein excretion and in shunt parameter as
a function of mean blood pressure (MBP) change induced by treatment
either with enalapril or irbesartan.
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 |
DISCUSSION |
The results of the present study show that in patients with IgA
nephropathy and normal or moderately impaired GFR, 4-wk treatment with
conventional doses of either enalapril (20 mg/day) or irbesartan (100 mg/day) significantly reduced mean blood pressure over
baseline. This reduction in blood pressure was, however,
transient, reaching the maximum effect 4-6 h after drug
administration; it did not last for the entire 24-h period. Trough
levels of blood pressure did not change significantly during both
treatments. Also, renal hemodynamic parameters did not change
significantly after 28 days of treatment, and no statistically
significant changes in GFR were observed between values measured before
and after treatment. A mild elevation in RPF was selectively induced by
irbesartan but not by enalapril treatment. This is in keeping with
previously reported data on the effect of ACE inhibition and ANG II
receptor antagonism on renal hemodynamics (11, 17, 18).
Despite the transient antihypertensive effect during the 24-h period,
urinary protein excretion was effectively reduced by both treatments,
to extents comparable to each other. Reductions in
urinary protein excretion over baseline values averaged 38.6 and
45.4%, respectively, for enalapril and irbesartan. Measurement of
size-selective function by the fractional clearance of graded-size neutral dextran molecules is instrumental to quantifying the effective amelioration of glomerular membrane barrier permeability by both drugs,
which can explain how present treatments reduced protein excretion. A previous study by our group (39), in which
patients with IgA nephropathy were studied sequentially before and
after treatment with enalapril, established that ACE inhibition in this disease ameliorated urinary protein excretion via a primary action on
intrinsic glomerular membrane permeability to
macromolecules. In this study, enalapril did not affect
the sieving coefficient of small, relatively permanent dextran
molecules (radii < 42 Å) but significantly reduced that of
larger dextran macromolecules (radii > 56 Å). That such
amelioration translated into reduction of glomerular filtration of
circulating proteins and in final urinary excretion was suggested by
findings of effective reduction in mean dimensions of the largest
pores, which are responsible for protein filtration (39), induced by
the drug administration. This previous study only allowed us to
speculate on the possibility that, in IgA nephropathy, enalapril
improved glomerular barrier size-selectivity by preventing
the formation of ANG II. This issue was explicitly addressed
by the current investigation, the results of which, in harmony with
previous experimental findings (40), first showed that neither drug
modified the sieving coefficient of small permeable neutral
dextrans, but both effectively reduced transglomerular
passage of larger macromolecules in this pathological condition in humans.
To quantify effective changes in intrinsic membrane permeability
properties induced by both treatments, we used a theoretical model of
glomerular size-selectivity. This model assumes that the glomerular
membrane is perforated by a restrictive pore population having
lognormal probability distribution of their radii and a nonselective
shunt pathway in parallel. We preliminarily verified that simulation of
fractional clearance data was more precise considering the
lognormal + shunt model, compared with the assumption of a lognormal
distribution alone, which we have used in other studies (36, 39). Using
the lognormal distribution alone, we calculated higher values of the
mean sum of squared errors between measured and calculated sieving
coefficient (data not shown) than we did using the lognormal + shunt model.
The effect of both drugs was to decrease in average the mean pore
radius and the spread of the lognormal distribution (see Table 3 and
Fig. 3), although this tendency did not reach statistical significance.
By contrast, both treatments significantly lowered the importance of
the shunt pathway; in fact, the shunt parameter
0 decreased in average >40
and 43% after enalapril and irbesartan treatment, respectively (in the
conservative hypothesis, the
P was not changed by the treatments).
These data would suggest once again that antagonism of ANG II is the
key mechanism by which ACE inhibitors exert beneficial effects on
glomerular size-selective function and consequently on glomerular
filtration and urinary output of plasma proteins. In our present study,
we directly measured size-selectivity but not charge-selectivity of the
glomerular membrane, because technical problems make the measure of
this latter function difficult in humans (20). In addition, recent experimental evidences would suggest that the size of selective membrane pores under normal conditions is smaller than the size of
albumin (32), indicating that size-selective dysfunction must be present for abnormal filtration of this protein. This observation would support the conclusion that the improvement of
glomerular size-selectivity we have observed with the two treatments in
this study is a sign of effective amelioration of permselective function toward circulating proteins. On the other hand, the observed changes in fractional clearance of large dextran molecules cannot account entirely for the more important reductions in fractional clearance and absolute excretion rate of albumin. Because it is unlikely that major differences in proximal tubular handling of albumin
are induced by the treatments, the extent of the amelioration of
albumin excretion suggest that, in addition to the size-selective function, the charge-selective function of the glomerular membrane must
also have been improved by both antihypertensive treatments.
That both enalapril and irbesartan exert a similar quantitative effect
of ameliorating membrane sieving coefficient and reducing urinary
protein excretion to a quite comparable extent in patients with IgA
nephropathy is consistent with previous animal experiments showing that
both an ACE inhibitor and a selective ANG II receptor (AT1) antagonist (at a dose that
lowers systemic blood pressure to a comparable extent) were equally
effective in preventing urinary proteins in rats genetically
predisposed to proteinuria and progressive renal dysfunction (37, 38).
These studies represent experimental proofs that the ACE inhibitors'
beneficial effects of preserving glomerular permselective function in
many models of renal disease (1, 3, 40, 54-56) and protecting from
progressive damage are essentially mediated by blocking the formation
of ANG II rather than by other hormonal systems simultaneously
activated by this class of drugs.
The results of previous investigations and of the study presented here
allow some interesting observations on the relation between
antihypertensive and antiproteinuric effects of either drug (or class
of compounds). It has been suggested that the beneficial antiproteinuric effect of ANG II antagonism may be dissociated with the
antihypertensive action of these therapies (16, 21, 41). Our present
results would suggest that, on the acute and chronic level, there is no
correlation between the antihypertensive effects of enalapril and
irbesartan and changes in glomerular hemodynamics and urinary protein
excretion (see Figs. 1 and 4). These results would further support the
already postulated notion that the antiproteinuric effect of ANG II
antagonism is nonhemodynamic, depending instead on the beneficial
effect of reducing this hormone's biological activity on cellular
functions that, at the glomerular capillary wall, result in
amelioration of the permselective function.
A growing body of evidence is available that indicates greater
proteinuria is associated with a faster GFR decline (47) and that
reduction in urinary proteins, independent of the reduction in blood
pressure, is associated with a subsequent beneficial effect on the
progression of renal disease (34). These findings corroborate the
hypothesis that enhanced protein traffic is not only a risk factor for
faster GFR decline but may also contribute pathogenically to
progression of renal disease (43). Controlled trials demonstrating
that, for comparable blood pressure reductions, agents that more
effectively decrease proteinuria are more renoprotective in the long
term (19) strongly suggest that antihypertensive therapy should not
simply be targeted to reduce blood pressure but possibly and more
importantly to minimize proteinuria as well. Furthermore, this evidence
and the present results indicate that minimizing blood pressure cannot
necessarily be the only or the ideal sensitive target of future
renoprotective strategies.
In summary, our investigation documented that ACE inhibition and ANG II
receptor antagonism comparably ameliorated urinary protein excretion
and glomerular size-selective function in IgA nephropathy. The
beneficial effects of the two drugs tested are not directly related to
changes in blood pressure and suggest that ANG II plays a key role in
the mechanism responsible for the development of glomerular membrane
dysfunction in this renal disease.
 |
ACKNOWLEDGEMENTS |
We thank Bogdan Ene Iordache for helpful assistance during data
collection and management.
 |
FOOTNOTES |
Part of this study was supported by a research grant from Sanofi
Winthrop, Gentilly Cedex, France.
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: A. Remuzzi, Dept. of Kidney Research,
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24123 Bergamo, Italy.
Received 22 June 1998; accepted in final form 17 November 1998.
 |
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