(Hypertension. 1995;25:981-985.)
© 1995 American Heart Association, Inc.
Articles |
Microalbuminuria and Erythrocyte Sodium-Hydrogen Exchange in Essential Hypertension
From Clinica Medica I and II, University of Pisa (Italy).
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Abstract |
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Abstract Microalbuminuria (urinary albumin excretion between 20 and 200 µg/min) and abnormalities of red blood cell sodium-hydrogen exchange coexist in essential hypertensive patients. To evaluate how the two phenomena relate, we recruited 10 untreated microalbuminuric male essential hypertensive patients without diabetes to be compared with an equal number of matched essential hypertensive patients excreting albumin in normal amounts as well as 10 healthy control subjects. Sodium-hydrogen exchange values were increased to a comparable extent in microalbuminuric and normoalbuminuric hypertensive patients. Systolic and mean blood pressures were higher in microalbuminuric patients. Fasting insulin was greater and high-density lipoprotein cholesterol lower in patients than control subjects. Urinary albumin excretion correlated positively with both mean blood pressure and left ventricular mass values in the absence of a relationship with circulating lipid and insulin levels. In contrast with microalbuminuria, sodium-hydrogen exchange covaried only with high-density lipoprotein cholesterol and insulin levels. Thus, microalbuminuria and an abnormal sodium-hydrogen exchange are unrelated phenomena in essential hypertensive patients. Microalbuminuria appears to be a hemodynamically driven biological variable, while an accelerated sodium-hydrogen exchange seems primarily conditioned by the metabolic abnormalities of hypertension, possibly in the context of an insulin-resistant syndrome.
Key Words: albuminuria • ion transport • insulin • lipids • hypertension, essential
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Introduction |
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Microalbuminuria is associated with a dysfunctional vascular endothelium1 and an increased left ventricular mass (LVM)2 in hypertensive patients and predicts cardiovascular events in nondiabetic subjects.3 4 Thus, this frequent abnormality in essential hypertension5 represents more than a sign of renal damage, of which an understanding is still incomplete. Evidence from insulin-dependent diabetics showed an important correlation between microalbuminuria and sodium-lithium (Na+-Li+) countertransport,6 a mode of operation of the sodium-hydrogen (Na+-H+) antiport, which regulates cell volume and growth.7 Greater urinary albumin excretion (UAE) and cardiac mass were also found in essential hypertensive patients, who were characterized by an elevated Na+-Li+ countertransport,8 a genetically determined system,9 and a possible inherited marker for cardiovascular complications of hypertension.10 Thus, microalbuminuria and an abnormal activity of the Na+-H+ exchange might be directly linked even in essential hypertensive patients. However, no data are available to confirm or negate this possibility.
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Methods |
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Subjects
We included carefully age-matched (±3 years) male subjects in the sample to exclude possible gender- and age-related confounders. Preliminary exclusion criteria were malignant or accelerated hypertension, congestive heart failure, body mass index greater than 30 kg/m2, diabetes (fasting glucose >7.8 mmol/L), previous myocardial infarction, or renal and connective tissue diseases. Normal serum creatinine (<106.8 µmol/L), urinary sediment, and urine culture were also required. Once a potential subject was identified, eligibility for the study was reserved for those with a good acoustic window for determination of echocardiographic parameters and an absence at Doppler examination of valvular lesions that might contribute to hypertrophy. Biochemical, urinary, and cardiac determinations were obtained at intervals not longer than 2 weeks. The final study sample included 30 men divided into the following three groups. Ten essential hypertensive patients with microalbuminuria (see below) underwent a full clinical, biochemical, and instrumental workup for secondary hypertension, including an angiographic procedure, if needed. Renal ultrasound scan showed normal-sized kidneys and no evidence of cortical scarring or obstructive uropathy. This group was matched with 10 essential hypertensive patients with normal UAE who underwent a similar diagnostic procedure. Patients had blood pressure (BP) values consistently greater than 140/90 mm Hg as outpatients and were taking no medications for at least 2 weeks. No patient had been on diuretics, ß-blockers, or other drugs that affect lipid profile. Ten healthy, age-matched subjects were the control group. A consistent portion of our hypertensive patients could not offer reliable data regarding family history of hypertension; therefore, we did not pursue this issue. The study was approved by the Institutional Review Committee; the procedures were explained in detail, and subjects consented to them.
Experimental Procedures
Systolic BP (SBP) and diastolic BP (DBP) (Korotkoff phase V)
were measured by mercury sphygmomanometer in the morning with
participants in a supine position. The reported value was the mean of
10 indirect recordings taken over a 30-minute period. Anthropometric
measurements (height and weight) were made after each participant had
removed his shoes and upper garments. Blood samples were obtained
between 8 and 9 AM after an overnight fast.
Red Blood Cell Na+-H+ Antiport
Red blood cell (RBC) Na+-H+ antiport
activity was quantified as amiloride-sensitive H+ efflux
from acid-loaded cells. In detail, blood was collected into heparinized
syringes, transferred into glass tubes, and centrifuged at
60g for 9 minutes at ambient temperature. Plasma and buffy
coat were aspirated and the cells washed three times with a buffer
containing cold isotonic saline solution and 5 mmol/L sodium phosphate,
pH 7.4 (cell-to-buffer ratio, 1:4). Then cells were spun at
1320g for 5 minutes at 4°C, the buffer and white cell
buffy coat were removed by suction, and the packed RBC pellets were
kept in ice until assay. A 0.2-mL nominal volume of packed RBCs was
added to 3.8 mL of a solution (measured osmolality, 285±7 mOsm/kg;
n=10) containing NaCl 150, KCI 1, MgCl2 1, and glucose 10
mmol/L incubated at 37°C for 5 minutes under magnetic stirring. The
medium was then acidified (pH 6.35 to 6.45) by HCl (0.2N in 150 mmol/L
NaCl), and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS,
0.2 mmol/L, Sigma Chimica) was added 5 minutes later to inhibit the
anion exchanger.11 After pH was raised to 7.95 to 8.00 by
0.05N NaOH, the medium acidification rate (expressed in micromoles per
liter of cells per hour) was assessed by a microelectrode (pHmeter,
model 691, Metrohm Ltd) at 10-second intervals for 1 minute in the
absence and presence of amiloride (0.5 mmol/L, Sigma), an inhibitor of
the Na+-H+ transport system.12 The
proton efflux differences in the two conditions
(
pH1-pH2) were multiplied by the buffer
capacity of the incubation medium (b, determined before each
experiment by titration with NaOH and HCl) and were corrected for the
actual cellular fraction in the suspension (m, 0.82±0.04,
n=15, preliminary measurements) and the incubation time (t)
according to the formula
(pH1-pH2)xbxm-1xt-1.13
The intra-assay coefficients of variation of 10 triplicate measurements of pH1, pH2, and buffer capacity were 5.3%, 6.6%, and 3.6%, respectively. The actual intracellular pH achieved during acidification was measured in suspensions (n=10 replicates) of packed RBCs lysed through double-distilled water as described by other authors.14 Cellular pH in media acidified at 6.35 to 6.45 U for 5 minutes was 6.44±0.05 U and did not change when the incubation time was prolonged up to 15 minutes. Cell volume (estimated as the ratio of the optical density of hemoglobin at 541 nm in a spectrophotometer [Kontron 860] and hematocrit [by micromethod]) was 2.78±0.05 in basal conditions and 2.85±0.1 (n=4 replicates) at 1 minute after acidification, ie, an average 2.5% increase from basal.
The present method for determination of RBC Na+-H+ exchange generates absolute values lower than those obtained by other researchers15 for at least two reasons. First, amiloride-sensitive H+ efflux is only a part (60% to 80%) of the total proton efflux from acid-loaded cells.14 Second, we measured proton efflux rate at an intracellular pH of 6.44, whereas the reaction Vmax can be assessed only at lower pH values.15 On the other hand, our milder cellular acidification procedure has the methodological advantage of avoiding the use of hypertonic media15 to prevent marked cell swelling induced by chloride redistribution in strongly acid media.
Urine Collections
To minimize the confounding influence of daily physical activity
and to facilitate the collection procedure, our outpatients collected
urine from 8 PM to 8 AM during three
consecutive days as already described.1 2 Urinary albumin
was measured by nephelometry (Istituto Behring SpA), with a detection
limit of 0.6 mg/dL and an interassay coefficient of variation of
3.5%.16 The elevated biological variability of UAE (34%,
average of 30 variation coefficients of triplicate urinary collections)
was confirmed1 2 even in this sample.
Echocardiographic Studies
Interventricular septal thickness (IVST), posterior wall
thickness (PWT), and chamber volumes were measured by monodimensional
and bidimensional echocardiograms (Hewlett-Packard Sonos 1000) with
2.5- and 3.5-MHz transducers as described in detail17 to
derive LVM according to the Penn Convention.
Metabolic Parameters
Blood glucose was measured by gluco-oxidase. Immunoreactive
insulin (IRI) concentrations were measured by radioimmunoassay (Sorin;
sensitivity, 2.5±0.27 µIU/mL; within- and between-assay variations,
5.5% to 6.6% and 6.2% to 9.7%, respectively; range, 5.1 to 130.8
µIU/mL). Serum concentrations of total and high-density lipoprotein
(HDL, after precipitation of low-density lipoprotein [LDL] and
very-low-density lipoprotein fractions through phosphotungstic acid and
magnesium chloride) cholesterol and triglycerides (average coefficient
of variation of control pool: 2%, 5%, and 2%, respectively) were
assessed by enzymatic colorimetric techniques (cholesterol
oxidase/peroxidase aminoantipirine and glycerol phosphate
oxidase/peroxidase aminoantipirine, Menarini, Divisione Diagnostici,
Firenze, Italy). LDL cholesterol was calculated as Total
Cholesterol-(HDL Cholesterol+Triglycerides/5).
Data Analysis and Statistics
RBC Na+-H+ exchange was an average of
proton efflux values measured every 10 seconds over 1 minute.
Microalbuminuria was defined as a value equal to or greater than 20
µg/min and less than 200 µg/min18 ; LVM was indexed for
height (grams per meter) to take into account the effect of body
weight. Mean BP (MBP) and body mass index were derived through standard
formulas.
Log transformation was applied to UAE, RBC Na+-H+ exchange, triglycerides, and IRI data, as these variables were distributed in a skewed manner. Descriptive statistics are arithmetic means±SD or medians with range for log-transformed data. Statistical analysis was based on the comparison among matched groups through one-way ANOVA and Duncan's multiple comparison test to check between-group differences. Correlation coefficients were calculated according to standard formulas; determination coefficients (r2) were used to quantify the amount of variability explained by the regression. Multiple regression analysis was performed conventionally by testing the statistical significance of each regression coefficient through t test and calculating 95% confidence limits. A value of P<.05 was chosen as statistically significant.
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Results |
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Median UAE was 10 µg/min (range, 7.9 to 12.1) and 10.7 µg/min (range, 6.4 to 17.7) in control subjects and nonmicroalbuminuric patients, respectively, versus 45 µg/min (range, 22.2 to 194) in microalbuminuric patients. RBC Na+-H+ exchange was elevated in hypertensive patients compared with normotensive subjects (P<.0001) irrespective of microalbuminuric status (Fig 1).
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SBP and MBP were greater in microalbuminuric than normoalbuminuric patients; DBP was comparable. LVM index, IVST, and PWT were increased to a comparable extent in the two groups of hypertensive patients compared with control subjects (Table 1). Overall (n=30), MBP values showed a statistically significant correlation with both UAE and RBC Na+-H+ exchange (Fig 2). However, the strength of the association differed markedly (UAE: r=.77, P<.00001, r2=.59; RBC Na+-H+ exchange: r=.36, P<.05, r2=.13). Furthermore, when hypertensive patients (n=20) were analyzed separately from normotensive subjects, the relationship held for UAE (r=.62, P<.003) but not for RBC Na+-H+ exchange (r=.19, P=NS). SBP behaved as MBP. A weaker but highly significant correlation was found between LVM index and UAE (r=.45, P<.01, n=30) but not RBC Na+-H+ exchange (r=.20). The behavior of IVST (UAE: r=.42, P<.02; RBC Na+-H+ exchange: r=.32, P=NS) and PWT (UAE: r=.41, P<.02; RBC Na+-H+ exchange: r=.28, P=NS) did not differ from that of LVM index.
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indicates control subjects; 
, nonmicroalbuminuric hypertensive
patients; and 
, microalbuminuric hypertensive patients; n=10 per
group.Fasting IRI (P<.03) was higher and HDL lower (P<.0001) in microalbuminuric and normoalbuminuric hypertensive patients than normotensive subjects. Blood glucose did not differ (Table 2).
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Total and LDL cholesterol and triglycerides were higher in microalbuminuric patients compared with both nonmicroalbuminuric patients and control subjects, although the differences in triglycerides did not achieve the formal limits of statistical significance (F2,27=2.9, P<.1) (Table 2). Significant correlations existed between UAE and total (r=.48, n=30, P<.008) and HDL (r=-.54, n=30, P<.001) cholesterol as well as triglycerides (r=.44, n=30, P<.01). However, when these variables were combined with MBP in a multiple regression analysis for evaluation of their independent contribution to UAE variability, only BP showed a statistically significant (P<.01) association.
HDL cholesterol (r=-.57, n=30, P<.001; Fig 3) and IRI (r=.38, n=30, P<.05) were significantly related with RBC Na+-H+ exchange, whereas total cholesterol (r=.24), LDL cholesterol (r=.30), and triglycerides (r=.28) were not.
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Discussion |
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This study confirms13 19 the accelerated rate of Na+-H+ exchange found in erythrocytes and in platelets,20 lymphocytes,21 and leukocytes22 of patients with essential hypertension with the use of methods different from ours. Thus, independently from the assay technique, circulating cells of hypertensive patients consistently show evidence of an abnormal Na+-H+ exchange. However, we did not examine the molecular mechanisms of this abnormality, its relationship with family history of hypertension, the possibility of women showing the same results as men, and the extent to which circulating cells reflect the involvement of extravascular tissues. An important finding of our study was the independence of the abnormal RBC Na+-H+ exchange from the concurrent UAE in our hypertensive patients. This contrasts with insulin-dependent diabetics,6 in whom microalbuminuria and BP levels were strongly associated with an increased Na+-Li+ efflux, a supposed mode of operation of the Na+-H+ antiport.7 Evidently, the relationship between microalbuminuria, BP, and cellular proton exchange differs in essential hypertensive patients versus insulin-dependent diabetics, at least to the extent that Na+-Li+ and Na+-H+ exchange share the same biological meaning. An apparent discrepancy emerged also with previous data obtained in essential hypertensive patients,8 in whom UAE tended to be higher if the Na+-Li+ exchange rate was activated. However, the low number of hypertensive patients with a normal RBC Na+-H+ antiport activity made those and our results not comparable. BP levels were greater in microalbuminuric patients and, as in other groups of subjects,1 2 18 23 correlated strongly with UAE. Although weaker, a statistically significant correlation also linked UAE and a long-term indicator of pressure load such as LVM index. This result confirms previous data,2 the biological importance of which is strengthened when the intrinsically elevated variability of UAE is considered. The tendency of UAE to reach pretreatment levels shortly after drug withdrawal24 might also concur with the lower strength of association with cardiac mass, a structural index of cardiovascular injury that takes a longer time to modify.25 As in larger scale studies,26 total and LDL cholesterol and triglycerides tended to cluster in higher concentrations in our small microalbuminuric group. However, a multiple regression analysis confirmed the predominant influence of pressure versus lipids on UAE.
If hypertensive microalbuminuria was primarily a hemodynamic correlate, RBC Na+-H+ exchange showed no relationship with pressure and wall thickness values. These data are not expected from a system supposedly involved in the cardiovascular restructuring process of hypertension.7 Rather, RBC Na+-H+ exchange was heavily influenced by the metabolic status of our hypertensive patients, who not surprisingly,27 showed abnormal lipid and insulin levels. The significant inverse correlation between RBC Na+-H+ exchange and HDL cholesterol levels is a second relevant result of our study, consistent with evidence collected on Na+-Li+ countertransport.28 29 At variance with HDL cholesterol, the relationships with total and LDL cholesterol and triglycerides did not achieve statistical significance, but we cannot discern whether the discrepancy is due to the small size of our sample or from the only partial similarity between Na+-Li+ countertransport and RBC Na+-H+ exchange.13 15 30 Thus, caution is needed in extrapolating further on this point. Abnormal HDL cholesterol levels may affect directly the membrane structure31 and therefore also its cationic transport systems. However, the activation of RBC Na+-H+ exchange might be a consequence of the elevated insulin, a hormone that can directly stimulate the antiport.32 In fact, as in other samples,33 even our hypertensive patients were characterized by elevated fasting insulin. This finding is consistent with both a reduced insulin clearance34 and insulin resistance, this latter a frequent occurrence in hypertension,35 although we did not perform insulin stimulation tests or clamp studies to evaluate more precisely these possibilities. It is interesting that insulin resistance and high Na+-Li+ countertransport and Na+-H+ exchange activity were associated in both essential hypertensive patients36 37 and normotensive diabetics.38 Finally, the comparable fasting insulin levels between hypertensive patients with elevated and normal UAE confirm2 that hyperinsulinemia and microalbuminuria are uncoupled phenomena in essential hypertensive patients. This conclusion does not seem to apply to diabetics, in whom microalbuminuria may have broader metabolic implications.39
In conclusion, RBC Na+-H+ exchange was abnormal in essential hypertensive patients irrespective of the concurrent UAE level. UAE was primarily related to hemodynamic variables such as BP and LVM index; lipid and insulin levels were not influential. In contrast, RBC Na+-H+ exchange was independent of the pressure load and influenced mainly by HDL cholesterol levels, possibly in the context of an insulin-resistant status.
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Footnotes |
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Reprint requests to Dr Roberto Pedrinelli, I Clinica Medica, University of Pisa, 56100 Pisa, Italy. E-mail idd@vm.cnuce.cnr.it.
Received July 18, 1994; first decision October 12, 1994; accepted December 27, 1994.
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