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Vol. 161 No. 12, June 25, 2001 |
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Review Article |
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Angiotensin II Subtype 1 Receptor Blockers and Renal Function
Robert Toto, MD
Arch Intern Med. 2001;161:1492-1499.
ABSTRACT
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Blood pressure reduction is the most significant factor in delaying
onset and progression of renal disease. Blockade of the renin-angiotensin
system (RAS) using angiotensin-converting enzyme inhibitors (ACEIs) delays
renal disease progression. More recently, agents that block the RAS by preventing
angiotensin II from binding to its subtype 1 receptor (ARBs) have been developed
in an effort to prevent deleterious consequences of pathologic levels of angiotensin
II and to reduce the adverse effects of RAS blockade associated with ACEIs.
Human studies with a variety of ARBs have clearly demonstrated the antihypertensive
and antiproteinuric efficacy of these agents in patients with progressive
renal diseases. Moreover, the effects of ARBs are similar or identical to
those of ACEIs. Ongoing long-term clinical trials are designed to determine
whether ARBs also preserve renal function similar to ACEIs. Specifically,
the role of ARBs in patients with hypertension and type 2 diabetes is being
evaluated in 3 large trials, including Appropriate Blood Pressure Control
in Diabetes—Part 2 With Valsartan, the Losartan Renal Protection Study,
and the Irbesartan Diabetic Nephropathy Trial. Definitive evidence of the
long-term protective effects of ARBs in chronic progressive renal disease
is expected from these important studies.
HYPERTENSION: SCOPE OF THE PROBLEM
Hypertension is a major public health problem. Serious and often fatal
complications, including stroke, myocardial infarction, and renal failure,
can develop if hypertension is not controlled. Hypertension is highly prevalent
in diabetic and nondiabetic populations. It is estimated that from 1996 through
1998, 50 million people (or 1 in 4 adults) in the United States had hypertension
defined as systolic blood pressure (BP) of at least 140 mm Hg or diastolic
BP of at least 90 mm Hg.1
The prevalence of hypertension varies among ethnic groups, ie, 32.4%
among non-Hispanic African Americans; 23.2% among non-Hispanic whites; and
22.6% among Mexican Americans.2 In general,
68% of the 50 million individuals with hypertension were aware of their diagnosis,
and 53% were treated with antihypertensives, but in only 27% was BP controlled
with medication to less than 140/90 mm Hg.3
Although public awareness of hypertension, its treatment, and its control
improved from 1976 to 1991, the rate of improvement in these variables has
subsequently leveled off.3-4 Consequently,
the US Department of Health and Human Services has set a goal to control elevated
BP in at least 50% of the population by the end of 2000.5
According to the United States Renal Data System, diabetes mellitus
is the number one cause of end-stage renal disease (ESRD). Hypertension develops
in most patients with diabetes during the course of their renal disease before
starting renal replacement therapy (dialysis or transplantation). Hypertension
is the second most common cause of ESRD, accounting for approximately 25%
of new cases.6 The Sixth Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC VI) recommends that elevated BP be reduced to less
than 140 mm Hg systolic and less than 90 mm Hg diastolic, and lower if tolerated.3 Lowering BP correlates with slowing of renal disease
progression, making control of hypertension in the presence of renal disease
essential. Consequently, the JNC VI currently recommends that BP in the presence
of renal insufficiency should be no higher than 130/85 mm Hg.3
In a recent analysis of several clinical trials on antihypertensive efficacy
in hypertensive diabetic patients, Grossman et al7
demonstrated that a combination of more than 1 drug is frequently required
to achieve BP control levels recommended by the JNC VI. Furthermore, in keeping
with JNC VI recommendations, their analysis suggested that combination therapy
may be more beneficial than monotherapy.7
This review presents data supporting the need to control high BP to
prevent progression of renal disease. In addition, it provides clinical data
suggesting the additive benefit of blocking the renin-angiotensin system (RAS)
while lowering BP. The discussion of blockade of the RAS will focus on the
role of angiotensin II (Ang II) subtype 1 (AT1) receptor blockers
(ARBs) in the prevention of progressive renal failure.
HYPERTENSION AND RENAL FAILURE
Progressive renal insufficiency leads to ESRD. Preliminary data for
1997 show that approximately 380 000 persons were treated for ESRD by
means of dialysis or kidney transplantation in the United States, with the
incidence of ESRD increasing annually from 1988.6
These statistics clearly indicate a substantial medical and economic burden
to the individual and the country. Approximately 80% of patients in whom renal
insufficiency progresses to ESRD are hypertensive during the course of the
disease,8 and it is believed that uncontrolled
hypertension accelerates the rate of progression in these individuals, regardless
of the cause of renal failure.
Data from large clinical trials and epidemiological studies indicate
that hypertension is an important risk factor for progressive renal disease.
The VA Cooperative Study,9 the Hypertension
Detection and Follow-up Program,10 and the
Multiple Risk Factor Intervention Trial (MRFIT)11
have demonstrated that hypertension is an important risk factor for progression
of renal disease. It is known that increasing age, African American race,
male sex, and family history are important risk factors for development of
ESRD attributed to hypertension. The severity of hypertension is directly
correlated with increased risk for ESRD. The effect of elevated BP on the
development of ESRD was demonstrated in men undergoing screening for entry
in MRFIT (Figure 1).11
During a 16-year period, 847 of the 332 544 men died of or were treated
for ESRD. High BP was a strong and independent risk factor for the development
of ESRD, with a graded relationship between risk and BP. Elevated systolic
BP was especially predictive, and a relatively small increase doubled the
risk for ESRD.11 Mild to moderate elevations
of BP correlated with renal disease, underscoring the need for control of
hypertension at all levels.11 In patients with
type 2 diabetes mellitus, there is an almost linear relationship between increase
in mean arterial BP and yearly decrease in glomerular filtration rate (GFR)
(Figure 2).12
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Figure 1. Cumulative incidence of end-stage
renal disease (ESRD) due to any cause, according to blood pressure category
in 332 544 men undergoing screening for the Multiple Risk Factor Intervention
Trial. Normal indicates within reference range. Reprinted with permission
from Klag et al.11 Copyright 1996, Massachusetts
Medical Society. All rights reserved.
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Figure 2. The rates of decline in glomerular
filtration rate (GFR) vs the mean arterial pressure of studies extending for
at least 3 years in patients with non–insulin-dependent diabetes mellitus
nephropathy. Reprinted from Bakris et al with permission from Elsevier Science.12
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IMPORTANCE OF LOWERING BLOOD PRESSURE IN RENAL DISEASE
Most large clinical trials of antihypertensive therapy have focused
on cardiac and cerebrovascular end points. Consequently, only a few clinical
trials have examined the effect of BP lowering on the progression of renal
disease in diabetic and nondiabetic patients. Early clinical trials in hypertensive
patients with renal insufficiency failed to show a significant benefit of
BP lowering on decline in GFR.13 However, the
target level of BP control in these studies was relatively high by present
standards. For example, among the small subset of patients undergoing repeated
measures of GFR during 3 to 5 years in the VA Cooperative Trial, mean treated
diastolic BP was lowered to 97 mm Hg in the active treatment arm vs 117 mm
Hg in the placebo arm. At 97 mm Hg, there were no differences in the rate
of decline in GFR.9 In contrast, more recent
clinical trials with lower target BP levels have demonstrated that lowering
BP in hypertensive patients at risk for or with overt renal disease preserves
renal function (Table 1). 14-25
As shown in Table 1, systolic
BP of about 130 mm Hg and diastolic BP of about 80 mm Hg were associated with
a beneficial outcome in most studies. In the only study, to our knowledge,
that focused specifically on hypertensive nephrosclerosis, our group demonstrated
that lowering systolic BP to a range of 120 to 130 mm Hg and diastolic BP
to a range of 70 to 80 mm Hg in patients with established renal failure and
at high risk for progression to ESRD was associated with a very slow mean
decline in GFR, similar to that observed with aging (approximately 0.8 mL/min
per year).15
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Table 1. Clinical Trials Demonstrating That Blood Pressure Lowering
Preserves Renal Function*
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IMPORTANCE OF REDUCING PROTEINURIA
Proteinuria has been studied extensively as a marker for progression
of renal disease.26 Individuals normally excrete
protein at the rate of less than 150 mg/d. Loss of protein in the urine at
a volume of greater than 200 mg/L becomes apparent by means of reagent test
strip findings. Under normal circumstances, urinary albumin excretion is less
than 30 mg/d; microalbuminuria refers to albumin excretion of 30 to 300 mg/d.27 Microalbuminuria is a marker of risk for progression
of nephropathy in patients with type 1 diabetes and of increased risk for
cardiovascular death in patients with type 1 and type 2 diabetes and hypertension.
Several clinical trials have shown that impaired renal function in patients
with high-grade proteinuria (>1 g/d) progresses at a faster rate than for
those with low-grade proteinuria ( 1 g/d).14, 26
For example, in more than 400 patients with nondiabetic nephropathy, renal
disease progression was slowed when protein excretion was less than 5 g/d,
but progressed more rapidly when the rate of proteinuria was higher.28 The acceleration of renal disease progression in
patients with types 1 and 2 diabetes correlated with the level of baseline
proteinuria.26 Even in patients with controlled
essential hypertension and no evidence of renal disease, the onset of proteinuria
was a marker of future decline of renal function.29
The Modification of Diet in Renal Disease Study14
demonstrated that baseline proteinuria was an independent risk factor for
progression of renal disease in nondiabetic patients, and the degree of proteinuria
reduction might be a measure of the effectiveness of BP control. In addition,
this study showed that lowering BP below the currently accepted goal to 125/75
mm Hg slows the decline in GFR, particularly in patients with proteinuria
of greater than 1 g/d.14 Consequently, the
investigators recommended that the BP goal for patients with proteinuria of
at least 1 g/d should be 125/75 mm Hg, whereas the goal for patients with
hypertension and renal insufficiency should be 130/85 mm Hg.3
INFLUENCE OF THE RAS
Knowledge of the basic physiological features of the RAS has greatly
expanded in recent years. It is now well established that in addition to systemic
Ang II production by the classic RAS,30 Ang
II can be produced locally by many tissues31
and synthesized by ACE-independent pathways. Furthermore, it has been shown
that the known physiologic effects of Ang II in humans are conferred by its
binding to the selective AT1 receptor, which is present in various
target tissues, including kidney, heart, brain, systemic vasculature, adrenal
gland, and liver.30 Angiotensin II binds to
the AT1 receptor on the cell surface of many cell types in these
organs. This results in tissue-specific effects of Ang II such as sodium reabsorption
in the proximal tubule and vasoconstriction of the efferent arteriole in the
kidney, aldosterone release from the adrenal gland, and increased inotropy
and chronotropy in the heart.30
In experimental animal models of chronic renal failure, local production
of Ang II is believed to play a pivotal role in the progression of hypertensive
renal diseases. Angiotensin II has multiple effects on renal function in the
failing kidney that can exacerbate renal disease, including elevation of glomerular
pressure, which is associated with systemic hypertension, proteinuria, and
glomerulosclerosis. In addition, Ang II induces hypertrophy of glomerular
and tubular cells, enhances proteinuria, and stimulates proliferation of fibroblast
and mesangial cells and secretion of collagen and extracellular matrix proteins.
These effects conspire to induce chronic irreversible renal damage. Clinical
and experimental data also indicate a role for renal Ang II production in
the development and progression of renal disease in humans.30
Most data supporting a role for the RAS in human renal disease are derived
from studies in patients with renal disorders treated with agents that inhibit
Ang II formation or block Ang II receptors. These studies generally show equivalent
reductions in BP and proteinuria when ACEIs and ARBs are compared.32-33 Recent evidence also indicates that
intrarenal Ang II production is important in humans with renal disease.34 The relative contribution of systemic vs intrarenal
Ang II production in the pathogenesis of human renal disease is unknown. In
1 study, it was estimated that ACE-independent pathways form approximately
40% of the Ang II that acts locally in the kidney.35
Regardless of the source, inhibition of Ang II production or its blockade
at the receptor level has profound effects on renal function.
EFFECTS OF ACEIs AND ARBs ON RENAL FUNCTION IN PATIENTS WITH RENAL
DISEASE
Among antihypertensive agents, ACEIs and ARBs are 2 important classes
that have an impact on the RAS. In addition to their BP-lowering effects,
it is well established that attenuating the effects of the RAS with ACEIs
affords renoprotection independent of systemic BP control in some but not
all studies (Table 1).16-19,23-24
Among other effects, interference with Ang II preferentially decreases vasoconstriction
of the efferent arteriole, resulting in decreased glomerular pressure. Minimizing
the effect of Ang II may also prevent its proliferative effects on the mesangium
and inhibit inflammation and fibrosis.36 Both
antihypertensive classes have been shown to afford renoprotection in animal
models of renal failure and in humans with renal disease. Long-term studies
designed to determine whether ARBs also preserve renal function are not yet
completed. However, the BP-lowering and antiproteinuric effects of ARBs and
ACEIs have been shown to be equivalent in patients with diabetic and nondiabetic
renal diseases (Table 2).
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Table 2. Renal Effects of ARBs in Humans With Renal Disease*
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ACEIs in Patients With Renal Disease
The conversion of inactive Ang I to vasoactive Ang II is inhibited by
ACEIs. This decreases Ang II levels and reduces systemic BP. Because of the
nonspecific substrates of ACE, the BP-lowering and renoprotective effects
of ACEIs may also be related to inhibition of bradykinin degradation, resulting
in increased bradykinin levels.45-46
This additional action may explain the continued antihypertensive activity
of ACEIs, despite the fact that in some instances, decreases in plasma Ang
II levels are not sustained with long-term administration.47
In this regard, local Ang II production via alternate enzyme pathways may
contribute to the rise in Ang II levels.30
At present, the JNC VI recommends ACEIs as first-line therapy in patients
with hypertension and renal dysfunction.3 Initial
data supporting the renoprotective effects of ACEIs were for patients with
type 1 diabetes with nephropathy and mild renal insufficiency, with or without
hypertension.18, 48-51
Angiotensin-converting enzyme inhibitors delayed the decline in renal function,
decreased proteinuria, and demonstrated a renoprotective effect independent
of BP reduction or control. Reduction in the risk for overt nephropathy in
patients with type 2 diabetes who are at risk was confirmed in the Microalbuminuria,
Cardiovascular, and Renal Outcomes substudy of the Heart Outcomes Prevention
Evaluation study.52 This renoprotection was
also demonstrated in patients with nondiabetic nephropathy.53-54
Moreover, ACEIs provide protection from cardiac death, the most common cause
of death in the population with ESRD.55
ARBs in Patients With Renal Disease
As previously noted, Ang II in humans acts through receptor subtypes
AT1 and AT2. The AT1 receptor is known to
mediate all of the known physiologic and pathologic effects of Ang II on cardiovascular
structure and function in adult humans.56-58
These effects include vasoconstriction, salt and water retention, aldosterone
release and subsequent hyperkalemia, and augmentation of sympathetic activity
critical to BP control. The ARBs prevent these responses to Ang II by blockade
of the AT1 receptor. They also prevent the long-term effects of
Ang II, including inhibition of cellular proliferation, which may affect important
complications of hypertension such as vascular and left ventricular hypertrophy
and the renal complication of glomerulosclerosis.59
By acting directly at the AT1 receptor, ARBs are purported to antagonize
the actions of Ang II more completely than ACEIs. Furthermore, additional
activity of ARBs may be related to stimulation of the AT2 receptor.
The importance of the AT2 receptor in the remodeling process within
the renal interstitium has been raised by recent observations in AT2 receptor–null mice during ureteral obstruction. The absence of
the AT2 receptor in these mice results in accelerated fibrosis
and collagen deposition in the interstitium.60
Blockade of the AT1 receptor allows Ang II to become available
for AT2 receptor stimulation, potentially resulting in vasodilation
and antiproliferation. The relevance of this effect has not been clearly demonstrated
in humans.
EFFECTS OF ACEIs AND ARBs IN EXPERIMENTAL RENAL DISEASE
Experimental data using diabetic rat models suggested that ACEIs and
ARBs have similar beneficial effects. Early studies using the ARB losartan
potassium demonstrated reduced BP, proteinuria, and glomerular injury in rats
with reduced renal mass.61 In rats with drug-induced
diabetes, the ACEI ramipril and the ARB valsartan lowered BP equivalently
and prevented the increase in urinary albumin excretion observed in untreated
animals.62 Both agents attenuated glomerular
structural changes similarly. In another experiment, the ACEI enalapril maleate
and the ARB candesartan reduced BP comparably and inhibited proteinuria, glomerulosclerosis,
interstitial fibrosis, and inflammation early in the course of treatment in
partially nephrectomized rats. However, only candesartan prevented the late
progression of glomerulosclerosis and interstitial fibrosis.63
Additional studies in a rat model of hypertensive nephrosclerosis have shown
that 22 weeks of treatment with the ACEI delapril hydrochloride or the ARB
candesartan produced equivalent renoprotection (reduction in proteinuria and
glomerulosclerosis) compared with untreated control rats.64
Similarly, in a study of uninephrectomized hypertensive rats, the ACEI enalapril
and the ARB irbesartan decreased BP to within the reference range, lowered
proteinuria, markedly reduced glomerulosclerosis, and decreased glomerular
capillary pressure while maintaining GFR. Conversely, hypertension, proteinuria,
and elevated glomerular capillary pressure developed in untreated rats.65 A study in spontaneously hypertensive rats showed
that the ACEI captopril and the ARBs telmisartan and losartan reduced BP similarly
and attenuated renal damage by significantly decreasing urinary albumin level
and glomerulosclerosis.66 In another study,
treatment of male diabetic Munich-Wistar Froemter rats with the ARB valsartan
or the ACEI benazepril hydrochloride resulted in normalized systemic and glomerular
capillary BP, prevention of proteinuria, and minimized glomerulosclerosis.67 Eprosartan mesylate, a newer ARB, has also been shown
to be renoprotective in 5 of 6 nephrectomy models of progressive renal disease
in rats.68 Taken together, these studies provide
strong evidence that the BP-lowering and renoprotective effects of ARBs are
comparable to those of ACEIs in a variety of animal models of chronic, progressive
renal disease.
RENAL EFFECTS OF ACEIs AND ARBs IN HUMANS WITH CHRONIC RENAL DISEASE
Short-term Studies
Recent clinical studies involving small numbers of patients with follow-up
ranging from 1 to 18 months demonstrated the effectiveness of ARBs in lowering
blood pressure and proteinuria in patients with chronic renal disease (Table 2).33, 37-44,69
In one study, losartan produced a fall in BP, a dose-related decline in proteinuria,
and improved renal hemodynamics with stable GFR in 13 hypertensive patients
with renal disease.37 In another study, losartan
alone or in combination with other antihypertensive agents decreased BP and
stabilized creatinine clearance and renal hemodynamics in 112 hypertensive
patients with mild to severe renal insufficiency or who were receiving hemodialysis.38 Losartan in doses of 50 to 100 mg/d was shown to
be equivalent to amlodipine besylate, 5 to 10 mg/d, in lowering BP but superior
to amlodipine in reducing proteinuria in nondiabetics with chronic renal disease.70 The effectiveness of valsartan was evaluated in 9
hypertensive patients with advanced renal failure.40
Valsartan produced significant and sustained BP lowering compared with placebo,
with no change in renal hemodynamics, and a 20% to 40% reduction in total
urinary protein and albumin excretion. In a larger study, valsartan and captopril
lowered BP and decreased microalbumin excretion significantly better than
placebo in 122 normotensive and treated hypertensive patients with type 2
diabetes and nephropathy.8, 41, 71
Combinations of ACEIs and ARBs in patients with hypertension and impaired
renal function have shown that combination therapy results in synergistic
effects to reduce proteinuria with or without concomitant synergistic reduction
in systemic BP.42-43 As can be
seen, most renal studies to date have been performed with losartan. Whether
newer agents will have a more powerful effect on renal function in patients
with hypertensive renal disease remains to be determined. At this time, there
are no studies comparing losartan directly with other ARBs on renal function.
Long-term Studies
Taken together, these studies in patients with chronic renal disease
show that ARBs effectively lower BP and reduce proteinuria similar to ACEIs.
However, the question remains as to whether the ARBs offer long-term renal
protection similar to the ACEIs in similar diseased populations. Several trials
are under way to answer this question. These trials include the Appropriate
Blood Pressure Control in Diabetes—Part 2 With Valsartan trial, which
is assessing the effects of intensive vs moderate BP control on nephropathy
in normotensive and hypertensive patients with type 2 diabetes72;
the Losartan Renal Protection Study, which is evaluating the renoprotective
effects of losartan in patients with type 2 diabetes and nephropathy73; and the Irbesartan Diabetic Nephropathy Trial, which
is comparing the effectiveness of irbesartan vs amlodipine vs placebo in preservation
of renal function and overall mortality in patients with type 2 diabetic nephropathy.74-75
SAFETY AND EFFICACY OF ARBs
The efficacy, tolerability, and safety of ARBs have been established
in clinical trials with other antihypertensive agents.71, 76
The ARBs provide once-a-day dosing with a profile of adverse effects comparable
to that of placebo,59 whereas the ACEIs have
been limited by the development of a dry cough, which is seen in 5% to 20%
of patients.77 Results of recently completed
clinical trials showed that ARBs are better tolerated than ACEIs, with fewer
patients terminating treatment prematurely.39, 78
The Evaluation of Losartan in the Elderly (ELITE) I Study was a randomized,
double-blind study designed to evaluate the safety and tolerability of the
oral ACEI captopril (50 mg 3 times daily) and the oral ARB losartan potassium
(50 mg/d). The primary end point of the trial was a persistent increase in
serum creatinine level of greater than 25% above baseline. After 18 months
of follow-up, the incidence of hypercreatininemia was 10.5% in both groups.
Thus, there was no difference in the incidence of persistent renal dysfunction
in elderly patients with symptomatic heart failure treated with captopril
compared with losartan .39 In ELITE II, survival
during 8 months of treatment with losartan was shown to be equivalent to captopril
in elderly patients with congestive heart failure. Losartan was better tolerated
than captopril.78
All agents that block the RAS, including ACEIs, ARBs, and aldosterone
receptor antagonists, may cause hyperkalemia, particularly in patients with
renal impairment. However, the incidence of hyperkalemia in several studies
using ARBs, including losartan and valsartan, indicate that the likelihood
of hyperkalemia is relatively low.33, 38, 42-43
In a crossover study involving patients with chronic renal disease, valsartan
compared with lisinopril did not significantly increase serum potassium levels.42 However, in a short-term study of patients with advanced
renal failure with or without hypertension, valsartan, 160 mg/d, as monotherapy
or in combination with benazepril (valsartan, 80 or 160 mg/d, and benazepril
hydrochloride, 5 or 10 mg/d) increased serum potassium levels.44
In general, the incidence and severity of hyperkalemia is lower in ARB compared
with ACEI-treated patients with chronic renal disease.33, 38, 42, 44
CONCLUSIONS
This review stresses the significance of hypertension as an etiologic
component in the development of renal failure. The evidence presented demonstrates
that control of hypertension slows the inevitable decline of renal function
after renal abnormalities are identified. The ARBs are effective and safe
antihypertensives. They selectively block AT1 receptors and have
potential advantages compared with ACEIs because of their safety and tolerability
profile. Data from short-term studies suggest that ARBs are equivalent to
ACEIs in prevention of progressive renal disease. However, this needs to be
confirmed in long-term clinical trials. Current ongoing studies have been
designed to establish the long-term impact of ARBs on renal function.
AUTHOR INFORMATION
Accepted for publication January 18, 2001.
Corresponding author and reprints: Robert Toto, MD, Patient-Oriented
Research in Nephrology, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd, Dallas, TX 75390-8856 (e-mail: robert.toto{at}utsouthwestern.edu).
From the Department of Medicine, University of Texas Southwestern Medical
Center, Dallas.
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