© 1995 American Heart Association, Inc.
Articles |
Renal and Systemic Transvascular Albumin Leakage in Severe Atherosclerosis
From Steno Diabetes Center, Gentofte, and The Copenhagen City Heart Study, Rigshospitalet University Hospital, Copenhagen, Denmark.
Correspondence to Jan Skov Jensen, MD, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark.
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Abstract |
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Abstract Microalbuminuria was recently proposed as a novel atherogenic risk factor. The pathophysiological link between microalbuminuria and atherosclerosis may be mediated through an increased generalized transvascular leakage of albumin. To investigate this hypothesis, urinary albumin excretion and clearance and systemic transvascular albumin leakage (TERalb) were measured in 23 patients with severe clinical atherosclerosis and 25 healthy controls. In addition, renal clearances of three other endogenous plasma proteins (IgG, IgG4, and ß2-microglobulin) and of creatinine were measured. Measurements of urine and serum proteins were done by enzyme-linked immunosorbent assays. TERalb was measured by the fractional disappearance rate of 125I-albumin from the total intravascular compartment in 1 hour after intravenous injection. Glomerular filtration rate was estimated as creatinine clearance. Urinary albumin excretion (geometric means [95% confidence intervals], 10.5 [6.1 to 18.3] versus 5.7 [4.7 to 6.9] µg/min; P<.05), fractional urinary albumin clearance (2.8 [1.6 to 4.8] x10-6 versus 1.3 [1.0 to 1.6] x10-6; P<.05), and TERalb (6.0 [5.5 to 6.5] versus 5.1 [4.5 to 5.8] %/h; P<.05) were higher in patients than in control subjects. Glomerular charge selectivity (ratio of IgG clearance to IgG4 clearance) was lower in patients than in control subjects (1.5 [1.1 to 2.0] versus 2.3 [2.0 to 2.6]; P<.05). These alterations were independent of blood pressure, glomerular filtration rate, tubular function, and smoking status. It is concluded that atherosclerotic vascular disease is associated with renal and systemic transvascular leakiness for albumin. Theoretically, such leakiness may in addition allow for an increased lipid insudation into the large vessel wall, thereby linking microalbuminuria to atherogenesis. The lower glomerular charge selectivity is suggestive of decreased concentration of anionic components in the vessel walls.
Key Words: atherosclerosis • microalbuminuria • urinary albumin excretion • systemic transvascular albumin leakage • glomerular charge selectivity
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Introduction |
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Among the numerous atherogenic risk factors, even the strongest have limited prognostic specificity at the individual level. Thus, intervention in populations characterized by a high risk factor level will include a large number of subjects who will never develop clinical vascular disease (the "prevention paradox").1 2 3 Therefore, methods for more specific identification of individuals at high risk for development of atherosclerosis are urgently needed.
Recent data suggest that microalbuminuria, a slight elevation of albumin excretion in the urine, is a potential atherogenic risk factor, or rather a marker of increased susceptibility to the atherogenic effects of conventional risk factors such as dyslipidemia. This proposal is based partly on prospective epidemiological investigations and partly on clinical physiological investigations: Yudkin et al4 observed a highly increased prevalence of atherosclerotic vascular disease (odds ratio, 7) and mortality rate (odds ratio, 24) among individuals with microalbuminuria compared with normoalbuminuric individuals. The latter finding was later confirmed by Damsgaard et al.5 6 To elucidate the pathophysiological mechanism linking microalbuminuria to development of atherosclerosis, a series of clinical physiological and metabolic measurements were performed in individuals with microalbuminuria who had not yet developed clinically present vascular disease. The main conclusion was that microalbuminuria reflects a systemic transvascular leakiness for albumin7 and is associated with reduced size selectivity and charge selectivity of the glomerular vessel wall.8 Theoretically, this leakiness may also allow for a higher degree of lipid insudation into the large vessel wall,9 10 11 thereby linking microalbuminuria to atherogenesis. If these alterations also exist in individuals with clinically present vascular disease, the hypothesis of microalbuminuria as an atherosclerotic risk factor would be further supported.
The aim of this study was to measure, in a group of individuals with severe clinical atherosclerosis and a control group of healthy individuals, (1) UAER and Cl-albumin; (2) TERalb, as expressed by the fractional disappearance rate of intravenously injected 125I-albumin from the total intravascular compartment; and (3) size selectivity and charge selectivity of the glomerular vessel wall.
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Methods |
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Patients and Control Subjects
All subjects studied were recruited from The Copenhagen City Heart Study, a population-based longitudinal study of atherosclerotic vascular disease and its known and potential risk factors.12 For The Copenhagen City Heart Study, about 20 000 randomly chosen inhabitants of a well-defined area of Copenhagen were invited to participate in a health examination. The sampling procedure and the study design are described in detail elsewhere.13 All participants 40 to 65 years old with a history of AMI who took part within the first 24 months (January 1, 1992, to December 31, 1993) of the third Copenhagen City Heart Study were invited to the clinical research unit of the Steno Diabetes Center if the following exclusion criteria were absent: (1) untreated arterial hypertension (systolic blood pressure
160 mm Hg
and/or diastolic blood pressure 95 mm Hg [World Health
Organization criteria]); (2) a history of diabetes mellitus; (3) a
history of renal disease; (4) a history of inflammatory rheumatic
disease; and (5) use of angiotensin-converting enzyme
inhibitors. This exclusion procedure left 43 subjects
eligible for study, of whom 23 (composing the AMI group) were willing
to take part. The nonparticipants and the participants had similar age
and sex distributions. At the examination date two additional exclusion
criteria were set up: (1) clinical signs of cardiac decompensation and
(2) fasting venous blood glucose concentration of 6.7 mmol/L or
greater; both criteria were absent in all 23 participants. These 23
subjects had had one to five AMIs 1 to 19 years previously, which were
confirmed by contact with the cardiology departments of
admission and the relevant general practitioners. At the
time of diagnosis, at least two of the following three criteria were
present in each subject: chest pain, electrocardiographic
alterations compatible with AMI, and significant elevation of
concentration of myocardial enzymes in blood. Nine had undergone
arterial bypass surgery (coronary, 7; both
coronary and iliac, 1; and carotid, 1). One had an internal
cardiac pacemaker implanted because of malignant arrhythmia. In
addition, 2 participants had had a stroke and 2 suffered from severe
intermittent claudication. Twelve were taking aspirin in antithrombotic
doses, 8 received antihypertensive medication (loop diuretics,
3; ß1-adrenergic receptor blockers, 2; and calcium
channel blockers, 2), 5 had regular need for
nitroglycerine, 1 was taking digitalis, and 2 were
taking cholesterol-lowering agents. A group of 25 randomly
chosen clinically healthy subjects who had similar age and sex
distributions and had undergone the same exclusion procedure served as
control subjects. None of these control subjects routinely took any
kind of medication, and none had any electrocardiographic signs of
myocardial ischemia. All subjects studied were Caucasian. The
participants gave their informed consent. The study conformed to the
principles outlined in the Declaration of Helsinki and was approved by
the Regional Ethics Committee.
Blood Sample Analyses
The participants arrived at the Steno Diabetes Center at 8:00
AM after a 10-hour fast and tobacco abstinence. All were
placed in a recumbent position, and a polytetrafluoroethylene
(Teflon) cannula was inserted in an antecubital vein on each side,
one for blood sampling and the other for injection. After 30 minutes at
rest, blood samples were drawn without venous stasis for the following
analyses: blood hemoglobin concentration, hematocrit, leukocyte
count, platelet count, erythrocyte sedimentation rate, serum sodium
and potassium concentrations (flame photometry), serum
creatinine concentration (colorimetric
method of Jaffé), and blood glucose concentration (Granutest,
Diagnostica, Merck). Serum insulin concentration was
measured by use of an ELISA method free of
cross-reaction14 ; serum total cholesterol, HDL
cholesterol, and triglyceride concentrations
were measured by use of enzymatic colorimetric methods
(CHOL CHOD-PAP, HDL-CHOLESTEROL PRECIPITANT, and
Triglycerides GPO-PAP, Peridochrom,
Boehringer-Mannheim GmbH, respectively); and serum
concentrations of albumin,15
ß2-microglobulin,16 IgG,17 and
IgG48 were measured by use of ELISA methods
(intra-assay and interassay variation coefficients were less than 5%
and less than 10%, respectively).
Measurements of Urinary Protein Clearances
A timed 2-hour urine sample was collected for measurements of
urine concentrations of albumin,15
ß2-microglobulin,16 IgG,17 and
IgG48 by use of the same ELISA methods as for
the measurements of the corresponding serum concentrations (intra-assay
and interassay variation coefficients were less than 5% and less than
10%, respectively). Urinary protein excretion rate and renal
clearance, the latter corrected for body surface area, during the
2-hour collection period were calculated. Molecular weight, Stokes
radius, and isoelectric point of the four measured plasma proteins
were, respectively, 69 000, 36 Å, and 4.7 to 5.5 for albumin;
156 000, 55 Å, and 5.8 to 7.3 for IgG; 156 000, 55 Å, and 5.5 to
6.6 for IgG4; and 11 800, 16 Å, and 5.8 for
ß2-microglobulin.18 Because the
IgG4 subclass is more anionic but of size and configuration
similar to the total IgG, the ratio Cl-IgG/Cl-IgG4
expresses SI, an index of renal charge selectivity. Similarly, Cl-IgG
expresses an index of renal size selectivity because IgG is
electrically neutral at normal plasma and urinary pH. In addition,
urine concentration of creatinine was measured (by use of
the colorimetric method of Jaffé), and
Cl-creatinine corrected for body surface area was taken as
an estimate of the glomerular filtration rate. Renal
fractional protein clearances were expressed as the ratio of urinary
protein clearance to Cl-creatinine.
Measurement of TERalb
After each subject had been at rest for 1 hour,
TERalb was measured as previously described by Parving and
Gyntelberg19 with minor modifications: 75 kBq of
125I-labeled human serum albumin (Code IFE-IT23S,
Kjeller) containing less than 1% of free 125I was injected
intravenously. Venous blood samples of 10 mL were drawn
without stasis in heparinized tubes before and 10, 15, 20, 30, 40, 50,
55, and 60 minutes after injection. After
centrifugation at 1500g for 10 minutes,
plasma radioactivity was counted in duplicate samples of 2 mL in a
Cobra Auto-Gamma Counting System Model 5005 (Packard Instruments Co).
The mean measurement of counts per minute at each time point was
corrected for total plasma protein concentration (Refractometer TS-B,
American Optical Company; coefficient of variation 0.5%) and plotted
versus time after logarithmic transformation. TERalb was
then calculated on the basis of the slope of the best linear curve
fitted by the least squares method, using the assumption that the
radioactivity declined monoexponentially with time.
Only measurements with a linear correlation coefficient of at least
80% and a standard error of TERalb not exceeding 1.5%/h
were accepted. Otherwise one outlier was allowed to be rejected so the
highest possible correlation coefficient above 80% and the lowest
possible standard error of TERalb under 1.5%/h could be
obtained. This rejection procedure was performed for 6 subjects: 1 in
the AMI group and 5 in the control group. In 1 subject (from the AMI
group), rejection of one outlier did not enable the criteria
(correlation coefficient 80% and standard error of
TERalb 
1.5%/h) to be fulfilled; consequently,
TERalb was not calculated in this participant. Plasma
volume was calculated from the total amount of injected radioactivity
divided by the plasma radioactivity at time zero as derived from the
intercept of the fitted line, and it was corrected for body surface
area.
Other Clinical Variables
Blood pressure was measured four times (two on each side) after
each subject had been at rest for at least 2 hours, and the average was
recorded. Hawksley's random zero sphygmomanometer and an
appropriately sized cuff were used. Height and weight were measured
without shoes and heavy clothing. Body mass index was calculated as
weight/(height)2 (kg/m2), and body surface area
(in m2) was calculated as 0.007184 x
weight.425 x height.725. The waist
circumference was measured midway between the lower rib margin and the
iliac crest and the hip circumference was measured at the level over
the greater trochanters, and the waist/hip ratio was calculated.
Smoking habits were categorized as never, previous, or current smoking; alcohol consumption as none, 20 or fewer beverages per week, or more than 20 beverages per week (one beverage equals approximately 12 g ethyl alcohol).
Statistical Analysis
Data on continuous scales are given by means with 95%
confidence intervals when normally distributed or by geometric means
with 95% confidence intervals when nonnormally distributed.
Categorical data are given by fractions with 95% confidence intervals.
Tests for differences between the two groups were performed by
Student's unpaired t test or by the 
2
test for continuous or categorical variables, respectively. The
inclusion of 23 and 25 subjects in the two groups gives an 80%
test-power (1-ß) to detect a difference at the P<.05
significance level (two-tailed) of around 0.80xSD for normally
distributed variables such as TERalb. Associations
between variables were tested by simple and multiple linear
regression analysis with backward elimination. Nonnormally
distributed variables on a continuous scale were logarithmically
transformed to approach the normal distribution before the
analyses. P values of less than .05 (two-tailed)
were considered of statistical significance. The analyses were
run on the personal computer statistics package SPSS for
Windows, version 6.0.
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Results |
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The two groups were similar with respect to age and sex (Table 1
). Blood hemoglobin concentration, hematocrit,
leukocyte count, platelet count, serum potassium concentration, and
fasting blood glucose concentration were similar in the two groups
(data not shown). In the AMI group, erythrocyte sedimentation rate was
higher (13 [8 to 18] versus 5 [3 to 7] mm/h; P<.05),
whereas serum albumin concentration (36.2 [34.9 to 37.5]
versus 38.8 [37.8 to 39.7] g/L; P<.01) and serum sodium
concentration (139 [138 to 141] versus 142 [141 to 143] mmol/L;
P<.001) were slightly lower than in the control group.
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Conventional atherogenic risk factors in the two groups are shown in
Table 1
. Systolic blood pressure was higher in the AMI group than in
the control group; diastolic blood pressure tended to be
higher, but the difference was not statistically significant. Moreover,
serum HDL cholesterol concentration was lower in the AMI
group than in the control group.
In the AMI group both UAER and renal fractional Cl-albumin was
higher than in the control group (Table 2 and Fig 1). TERalb was also higher in the AMI group
than in the control group (Table 2 and Fig 2).
Cl-creatinine was similar in the two groups (Table 2).
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In the AMI group, fractional Cl-IgG4 was significantly
higher than in the control group; fractional Cl-IgG tended to be higher
in the AMI group, but the difference was not statistically significant
(Table 3). SI was lower in the AMI group than in the
control group (Table 3 and Fig 3).
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Fractional Cl–ß2-microglobulin was similar in the two
groups (Table 3). This was also the case when subjects with urinary pH
of less than 6.0 (3 in the AMI group and 5 in the control group) were
excluded from the analysis.
The associations between clinically present vascular disease and UAER, fractional Cl-albumin, and SI were all independent of, respectively, blood pressure, fractional Cl–ß2-microglobulin, and Cl-creatinine. The association between vascular disease and TERalb was independent of blood pressure and smoking status. Current tobacco smoking was independently associated with increased TERalb (r=.28; P<.05), whereas blood pressure and TERalb were not correlated.
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Discussion |
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This study has primarily shown that the urinary excretion and fractional Cl-albumin, as well as TERalb as measured by the fractional disappearance rate of albumin from the total intravascular compartment, were elevated in a group of individuals with severe clinical atherosclerosis compared with healthy individuals.
The observations support the hypothesis that the link between microalbuminuria and development of atherosclerotic vascular disease is mediated through a generally increased TERalb. Obviously, a cause-effect relationship between increased UAER, fractional Cl-albumin, and TERalb on the one hand and clinical atherosclerosis on the other cannot be deduced from the present cross-sectional study design. However, in clinically healthy individuals, UAER and TERalb are positively and independently correlated, suggesting that microalbuminuria reflects an increased TERalb previous to development of symptomatic atherosclerosis.7 Despite this, it can of course not be totally precluded that widespread atherosclerosis exists prior to elevation in UAER and TERalb.
Although most of the TERalb may take place in the capillaries, studies in animals showed a similar transport mechanism of albumin from the bloodstream across the endothelium in capillaries and in arteries.9 Moreover, in animal models the transendothelial efflux of albumin and lipids was highly correlated,10 and both were elevated in atherosclerosis.11 Although these observations cannot be directly extrapolated to humans, and although there are no prospective data regarding the predictive atherogenic effect of increased TERalb, it can be hypothesized that increased TERalb as reflected by increased albumin excretion in the urine is associated with a higher degree of lipid insudation into the inner arterial wall.
The physiological mechanisms and assumptions upon which measurement of TERalb is based and the interpretation of the quantity were earlier described in detail by Parving.20 TERalb may express the product of transvascular permeability of albumin and endothelial surface area. The possibility of the latter's being elevated in the AMI group is unlikely because plasma volumes were similar in the two groups under study. Moreover, urinary loss of albumin was negligible (around 0.01%) compared with the overall disappearance of albumin from the total intravascular compartment. Current tobacco smoking correlated positively and independently with TERalb, which confirms previous observations in healthy individuals.7 21 However, adjusting for smoking status did not abolish the significant association between atherosclerotic disease and elevated TERalb. TERalb is also elevated in conjunction with other atherogenic risk factors such as arterial hypertension and diabetes mellitus.19 22 23 However, in the present study, blood pressure, which was less than 160/95 mm Hg in all participants, treated or untreated, did not correlate with TERalb, although it was slightly higher in the AMI group than in the control group. Patients with diabetes mellitus were excluded from the study.
Still other factors may be responsible for the systemic and the renal transvascular leakiness for albumin in atherosclerosis. In the present study, the SI, as calculated from the ratio of Cl-IgG to Cl-IgG4, was reduced in the AMI group. In addition, there tended to be a loss of renal size selectivity as expressed by fractional Cl-IgG in the AMI group, but statistical significance was not reached. These alterations and the increased fractional Cl-albumin may very likely be of glomerular origin, because fractional Cl–ß2-microglobulin was similar in the two groups under study. It is thereby assumed that a certain decline in tubular reabsorption is reflected by increased renal clearance of the freely filtered ß2-microglobulin,24 and that IgG and IgG4 are similarly handled in the tubular system. Furthermore, the alterations were independent of blood pressure and glomerular filtration rate. This may be suggestive of independence of transcapillary hydrostatic pressure in the glomeruli, although it cannot be totally ignored as a contributor of the alterations.25 Because the IgG4 subclass is more anionic but of the same size and configuration as the total IgG, the observation of reduced SI (Cl-IgG/Cl-IgG4) may be explained by reduced amounts of anionic components in the glomerular filtration barrier.
The glomerular filtration barrier is constituted of the endothelial cell layer, the basement membrane, and the epithelial cell layer. Filtration of plasma proteins is mainly restrained by the porous basement membrane, which consists of extracellular matrix: ie, collagen IV, laminin, fibronectin, and heparan sulfate proteoglycan.26 The negative electric charge of the glomerular filter is mainly represented by heparan sulfate proteoglycan,27 which is structurally and functionally related to heparin.28 29 In addition, experimental removal of heparan sulfate from rat glomeruli elevates urinary albumin excretion.30 Therefore, the finding of decreased SI in addition to increased renal transvascular albumin leakage (UAER and Cl-albumin/Cl-creatinine) suggests that severe atherosclerosis is associated with decreased concentration of heparan sulfate in the glomerular filtration barrier. The question is whether this presumptive structural alteration is generalized, involving the large vessel walls. Previous human studies showed reduced concentration of heparan sulfate in the walls of the atherosclerotic aorta31 and coronary arteries,32 as well as a strong negative correlation between the accumulation of lipids and the concentration of heparan sulfate in aortas.33 Reduced concentration of heparan sulfate on endothelial cell surfaces and in interendothelial clefts and basement membranes underlying the endothelium might imply an increased generalized transvascular leakiness for albumin. These ideas were previously formulated by Deckert et al.34
A generalized dysfunction of the endothelial cell would offer an alternative explanation of the systemic and the renal transvascular leakiness for albumin in atherosclerosis. Thus, markers of endothelial dysfunction such as von Willebrand factor, tissue plasminogen activator, and plasminogen activator inhibitor appear to be elevated in atherosclerosis.35 36 37 However, in a recent study of clinically healthy subjects no association was found between UAER and markers of endothelial dysfunction.38
Only a few of the conventional atherogenic risk factors such as blood pressure and serum HDL cholesterol concentration were significantly altered in the AMI group in the present study. It is most likely explained by the cross-sectional study design, because individuals who survived AMI a priori may have had less pronounced atherogenic alterations than individuals who did not survive. In addition, the survivors may have changed their lifestyles. These considerations further emphasize the relevance of the present results regarding TERalb and renal protein clearance and their roles in atherogenesis.
In conclusion, clinically present atherosclerotic vascular disease is associated with renal and systemic transvascular leakiness for albumin. It is hypothesized that such systemic leakiness may involve the large vessels and allow for an increased lipid insudation into the arterial wall, thereby linking microalbuminuria to atherogenesis. The cause of this leakiness is unknown. The reduced charge selectivity of the glomerular vessel wall is suggestive of reduced concentrations of negatively charged components such as heparan sulfate in the extracellular matrix of atherosclerotic vessel walls.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Danish Heart Foundation and the Danish Medical Research Council (12-2008-1). Marja Deckert, Hanne Foght, and Karina Skou, Steno Diabetes Center, Gentofte, Denmark, are thanked for their expert technical assistance. Dr Gorm Jensen (The Copenhagen City Heart Study, Rigshospitalet University Hospital, Copenhagen, Denmark), Dr Knut Borch-Johnsen (Department of Cardiology C, Copenhagen County Hospital, Glostrup), Dr Bo Feldt-Rasmussen (Department of Nephrology and Endocrinology P, Rigshospitalet University Hospital, Copenhagen), and Dr Torsten Deckert (Steno Diabetes Center, Gentofte, Denmark), are thanked for valuable discussion.
Received January 10, 1995; accepted June 19, 1995.
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