European Heart Journal Supplements (2003) 5 (Supplement F), F12—F18

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Renal involvement in hypertensive cardiovascular
disease
A. M. Sharma
McMaster University, Hamilton, Ontario, Canada

Cardiovascular morbidity and mortality are elevated in renally impaired patients,

KEYWORDS
Angiotensin II receptor especially if they are hypertensive. Diabetes is also associated with a high
blockers; prevalence of cardiovascular morbidity and end-stage renal disease. Albuminuria,
Nephropathy; elevated serum creatinine, decreased creatinine clearance and proteinuria
Renin—angiotensin— independently predict cardiovascular risk. Even patients with mild renal impairment
aldosterone system; should be treated to slow kidney disease progression and reduce vascular damage.
Renoprotection; Blood pressure control is effective in reducing vascular complications of diabetes,
Telmisartan
but not all classes of antihypertensive agents provide renoprotection. Angiotensin-
converting enzyme inhibitors are superior to beta-blockers in preventing or delaying
the loss of kidney function associated with hypertension. The renoprotection
appears to be in part independent of the antihypertensive effect. Angiotensin II
receptor blockers (ARBs) also reduce the risk of renal complications in diabetics.
Telmisartan seems well suited to provide renoprotection because, unlike other ARBs,
it is almost exclusively excreted by the liver and no initial dose adjustment is
required for patients with mild-to-moderate renal impairment. Other advantages of
telmisartan include its very high volume of distribution and long terminal
elimination half-life. Clinical trials to evaluate telmisartan will address the problems
of diabetes, renal impairment and end-organ disease.
© 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All
rights reserved

Introduction decline in the prevalence of conventional

End-stage renal disease (ESRD) is a major global
public health problem. In the U.S.A. alone there
are currently about 300 000 patients with ESRD,
and the prevalence is increasing annually at a rate
of about 7%.1 Thus, by the year 2010, in the U.S.A.
more than 650 000 patients will be receiving
treatment for ESRD. Epidemiological data suggest
that the increase in prevalence is seen despite the
Correspondence: Arya M. Sharma, MD, Canada Research Chair
for Cardiovascular Obesity Research & Management, McMaster
University, Hamilton, Ontario, Canada
cardiovascular risk factors, such as hypertension,
hypercholesterolaemia and smoking, but parallels
an increase in diabetes (Fig. 1).1
Indeed, the single most important cause of ESRD
in the Western world is diabetic nephropathy.2
Health statistics clearly point to an epidemic of
type 2 diabetes.3 According to Medicare records of
treated ESRD between 1994 and 1996, 41% of the
total incidence by primary diagnosis was
attributable to diabetes and 28% was ascribed to
hypertension, with the remaining 31% due to
glomerulonephritis, cystic kidney disease, other
urological diseases or other (including unknown)

01520-765X/03/0F0012 + 07 $35.00/0 © 2003 The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.
Nephropathy and cardiovascular disease
Fig. 1 Prevalence of cardiovascular risk factors and end-stage renal disease (ESRD). Sources of data: National Health and Nutrition
Examination Survey I, II and III, National Center for Health Statistics and United States Renal Data System.1
causes.4 An ageing population is another important
explanation for the increasing prevalence of ESRD.
With respect to the two primary causes of ESRD,
namely diabetes and hypertension, obesity is
thought to be responsible for 85—90% of diabetes
cases and 65—75% of hypertension cases.5
Furthermore, obesity-related glomerulopathy is
regarded as an emerging epidemic.6 Over the
period 1986—2000, there has been a 10-fold
increase in the incidence of obesity-related
glomerulopathy, defined as glomerulomegaly with
or without focal segmental glomerulosclerosis.
Prognostic implications of renal disease
The public health problem attributable to diabetic
nephropathy is exacerbated because the incidence
of cardiovascular morbidity and mortality is very
high in patients with ESRD.7 United States Renal
Data System statistics for 1994—1996 show that the
incidence of cardiovascular mortality increased
linearly in the general population with increasing
age, but was uniformly higher, regardless of age,
for dialysis patients.6 In addition, the increase in
mortality with age was steeper in dialysis patients.
In ESRD patients starting dialysis therapy, survival
rates vary depending on the underlying pathology.
Those with left ventricular systolic dysfunction
generally fared poorly, with few survivors beyond
5 years (Fig. 2).8 Patients with left ventricular
dilatation and concentric left ventricular
hypertrophy tended to have a somewhat better
survival rate, but the prognosis was likewise poor
compared with dialysis patients with no left
ventricular disorders. Similarly, patients beginning
dialysis therapy had a median survival of only
F13
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44 months if they also had ischaemic heart disease,
as compared with 56 months if there was no
ischaemia.9 The median times to the onset of heart
failure were 24 and 55 months, respectively. The
effect of the presence of ischaemia was highly
significant (P=0.0001).
Microalbuminuria (a proposed marker of
generalized vascular damage) is an important
predictor of the development of severe nephro-
pathy and cardiovascular mortality in patients
with chronic renal failure, cardiovascular disease
or diabetes mellitus.10—12 Increased serum
creatinine (≥140 µmol/l), decreased creatinine
clearance and decreased glomerular filtration rate
(<44 ml/min) are associated with increased
cardiovascular risk.13 After adjusting for age, sex,
glucose tolerance, hypertension, cardiovascular
disease and other risk factors, low-density
lipoprotein cholesterol, homocysteine, albuminuria,
von Willebrand factor, soluble vascular adhesion
molecule-1 and C-reactive protein, an inverse
association has been identified between renal
function and cardiovascular mortality in a general
middle-aged to elderly population.
Results of the Systolic hypertension — Europe
(Syst-Eur) study14 likewise indicate that higher
levels of serum creatinine and trace or overt
proteinuria are associated with an increased
number of cardiovascular events and higher
mortality in patients aged 60 years or older with
isolated systolic hypertension (systolic blood
pressure 160—219 mmHg and diastolic blood
pressure <95 mmHg). Even when adjusted for age,
sex and various other covariates, elevated serum
creatinine was associated with a worse prognosis.
There are also data to suggest that the
combination of microalbuminuria (30—300 mg
F14
Fig. 2 Cumulative percentage survival in patients starting dial-
ysis therapy according to the presence of left ventricular dys-
function.8 LV, left ventricular; LVH, LV hypertrophy. Reprinted
from Parfrey PS, Foley RN, Harnett JD, et al. Outcome and risk
factors for left ventricular disorders in chronic uraemia.
Nephrol Dial Transplant 1996;11:1277—85, by permission of
Oxford University Press.
urinary albumin excretion per 24 h) with ST—T
segment changes on a resting ECG can identify
those at significantly increased risk for all-cause
and cardiovascular mortality.15 The risk when ST—T
segment changes were present in the absence of
microalbuminuria was approximately fourfold lower.
In a study of 1906 patients with congestive
heart failure, classified as New York Heart
Association class III or IV, impaired renal function
(as measured by baseline glomerular filtration
rate) was a stronger predictor of mortality than
was impaired cardiac function (as measured by
left ventricular ejection fraction).16 The lack of
correlation between low baseline glomerular
filtration rate and left ventricular ejection
fraction suggests that reduced cardiac output is
not primarily responsible for impaired renal
function.
It must, however, be noted that a recent meta-
analysis of longitudinal studies from 1973 to 1999
concluded that moderate renal insufficiency
(defined as a serum creatinine concentration of
104—146 µmol/l in women and 122—177 µmol/l in
men) was not an independent risk factor for
cardiovascular disease in the general population
(Fig. 3).17 It was, therefore, proposed that
correlations found in other studies were likely to
be due to co-occurrence of renal insufficiency
with traditional cardiovascular risk factors, such
as age, hypertension and previous cardiovascular
disease. Thus, in a cross-sectional study of 369
patients with chronic renal impairment, patients
with even mildly elevated serum creatinine
(<186 µmol/l) had, on average, higher serum
triglycerides, lower high-density lipoprotein
A.M. Sharma
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Fig. 3 Relationship between impaired glomerular filtration rate
and mortality in patients with heart failure (New York Heart
Association class III or IV).16 Reprinted with permission from
Lippincott Williams & Wilkins (Circulation 2000;102:203—10).
cholesterol and higher serum homocysteine than
did age- and sex-matched control individuals with
established coronary artery disease but normal
creatinine levels.18 Also, in the patients with mild
renal impairment there was a higher incidence of
hypertension and left ventricular hypertrophy.
In a 10-year follow-up study of 503
predominantly non-insulin-dependent diabetic
patients, after correction for other independent
risk factors (age, serum creatinine level and
known duration of microalbuminuria), a urinary
albumin concentration greater than 1.5 µmol/l
was associated with a hazard ratio of 1.53—2.28
for mortality.19 Again, risk factors that
significantly correlated with urinary albumin
excretion were age (P<0.05), duration of
microalbuminuria (P<0.01), systolic blood pressure
(P<0.01), serum creatinine (P<0.001) and fasting
plasma glucose (P<0.01).
Role of angiotensin II in renal
impairment
Normally functioning kidneys maintain constant
intraglomerular pressure by an autoregulatory
mechanism that adjusts to variations in mean
arterial pressure.20 In chronic hypertension with
normal renal function, this autoregulation still
takes place over the range of more elevated
arterial pressures (Fig. 4). By contrast, in chronic
hypertension accompanied by chronic renal
disease, intraglomerular pressure escapes from
autoregulation and increases fairly continuously
with arterial pressure. The renin—angiotensin—
aldosterone system (RAAS) plays a pivotal role in
this regulatory process.21
Nephropathy and cardiovascular disease
In diabetic nephropathy, the effects of
angiotensin II have been explained by a number of
mechanisms.22 The proposed haemodynamic effects
include raising systemic hypertension, eliciting
systemic and renal vasoconstriction, causing
increased glomerular capillary pressure and
permeability, and causing mesangial cell contraction
leading to reduction in filtration surface area.22
Possible non-haemodynamic effects include
induction of renal hypertrophy and cell prolifera-
tion, stimulation of extracellular matrix synthesis,
inhibition of extracellular matrix degradation,
stimulation of cytokine production (e.g. tissue
growth factor-gamma, vascular endothelial growth
factor and endothelin, which all can contribute to
end-organ damage) and stimulation of superoxide
production.22 These and other, more general effects
of angiotensin II (such as macrophage activation,
inflammation and induction of proteinuria) support
the peptide’s central role in the pathogenesis of
progressive renal injury.23
Impact of antihypertensive therapy
A meta-analysis of studies lasting at least 3 years
and involving patients with type 2 diabetic
nephropathy found that lowering mean arterial
blood pressure to levels well below systolic/
diastolic blood pressure of 130/85 mmHg was
associated with a slower decline in renal function
(as measured by glomerular filtration rate).24
A study of type 2 diabetes, namely the United
Kingdom Prospective Diabetes Study (UKPDS),25,26
showed that tight control of blood glucose (using
either sulphonylureas or insulin to a fasting plasma
glucose concentration <6 mmol/l) or of blood
pressure (using an angiotensin-converting enzyme
[ACE] inhibitor or a beta-blocker) to below
150/85 mmHg independently reduced the risk (by
up to 37%) of diabetes-related death, any
diabetes-related end-point and all microvascular
end-points. Stringent blood pressure control was
also associated with a significant reduction (—44%;
P=0.013) in stroke incidence. Surprisingly, the risk
for macrovascular disease did not change as a
result of glucose or blood pressure control, in
contrast to the documented reduction in the risk
of microvascular complications.
However, another analysis of the UKPDS data
showed that, for each 10 mmHg decrease in mean
systolic blood pressure, there was an
accompanying risk reduction of between 12% and
19% for myocardial infarction, stroke, heart
failure, microvascular end-points, lower extremity
amputation, any diabetes-related end-point,
F15
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Fig. 4 Maintenance of intraglomerular pressure by renal
autoregulation despite variations in mean arterial pressure.20
Palmer BF. Renal dysfunction complicating the treatment of
hypertension. N Engl J Med 2002;347:1256—61. Copyright
© 2002. Massachusetts Medical Society. All rights reserved.
diabetes-related death and all-cause mortality.27
An essentially linear relationship was found
between systolic blood pressure over the range of
110—170 mmHg and risk reduction for diabetes-
related end-points and for diabetes-related and
all-cause mortality.
Because of the importance of the RAAS in renal
hypertensive disease, its blockade is likely to be
an essential component of treatment for patients
with impaired renal function.28 Results from the
Heart Outcomes Prevention Evaluation (HOPE)
study29 indicate that the primary trial outcome
occurred with a higher incidence (22% vs 15%;
P<0.001) in patients with, as compared with those
without, mild renal insufficiency quantitated by
baseline serum creatinine concentration. This
effect was independent of known cardiovascular
risks and treatment. The ACE inhibitor ramipril
reduced the incidence of the primary end-point of
this trial (cardiovascular death, myocardial
infarction or stroke) both in patients with and in
those without renal insufficiency (hazard ratio
0.8). For all patients, risk increased significantly
with increasing serum creatinine concentration
(risk ratio 2.34 for a 88.4 µmol/l increase in serum
creatinine between quartiles; Fig. 5).
In diabetic patients, Microalbuminuria,
Cardiovascular and Renal Outcomes in HOPE
(MICRO-HOPE)30 showed that ramipril brought
about a risk reduction (relative to placebo) of 24%
in total mortality, 37% in cardiovascular death,
22% in myocardial infarction, 33% in stroke, 17% in
revascularization and 24% in overt nephropathy (as
measured by the urinary albumin/creatinine
ratio). The microvascular outcomes (diabetic
nephropathy and renal failure) were reduced by
ramipril to nearly the same extent as were the
cardiovascular outcomes.
F16
Use of angiotensin II receptor blockers
in the renally impaired
More complete inhibition of the RAAS may be
possible with an angiotensin II receptor blocker
(ARB). The ARBs bind specifically to the
angiotensin II type 1 (AT1) receptor, which is
believed to play a cental role in the pathogenesis
of renal disease.31 As a consequence, angio-
tensin II, whether formed by the converting
enzyme or by other enzymatic pathways, is no
longer able to stimulate the AT1 receptor.
The Irbesartan in Diabetic Nephropathy Trial
(IDNT)32 enrolled 1715 patients with hypertension,
type 2 diabetes and proteinuria (900 mg/day).32
Double-blind treatment consisted of placebo, the
calcium channel blocker amlodipine or the ARB
irbesartan, with an average follow-up of
2.6 years. Adjunctive antihypertensive therapies
(excluding ACE inhibitors, ARBs and calcium
channel blockers) could be added to all groups to
help achieve blood pressure goals (systolic/
diastolic blood pressure 135/85 mmHg). The
primary composite end-point of the trial was the
time to doubling of serum creatinine, ESRD or
death. Irbesartan was significantly superior to
placebo, with a relative risk reduction of 20%
(P=0.02), and to amlodipine, with a relative risk
reduction of 23% (P=0.006) in prolonging the time
to the composite end-point. Serum creatinine
increased 24% more slowly in patients treated with
irbesartan than in those treated with placebo and
21% more slowly than in the amlodipine group.
Irbesartan was also superior to both placebo and
amlodipine in reducing the risk of ESRD.
The Reduction of Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan (RENAAL)
trial,33 using the same primary composite end-
point of doubling of serum creatinine, ESRD or
death as was used in IDNT. It showed that 16%
(P=0.02) fewer patients treated with the ARB
losartan compared with placebo reached one of
these end-points during the trial period, which
lasted for a mean of 3.4 years.
Telmisartan in management of renal
disease
Telmisartan is an ARB that should be particularly
appropriate for providing renoprotection. Unlike
other ARBS, which are mainly excreted via the
kidneys,34 telmisartan is almost exclusively
excreted by the liver.35 In patients with mild-to-
moderate hypertension and moderate renal
impairment, telmisartan was shown to be safe and
A.M. Sharma
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Fig. 5 Primary outcome according to quartiles of serum creati-
nine concentration.29 Quartiles were <82.2 µmol/l, 82.2—
96 µmol/l, 96.1—107.9 µmol/l and ≥108 µmol/l. Reprinted with
permission from the American College of Physicians—American
Society of Internal Medicine (Ann Intern Med 2001;134:629—36).
effective in controlling blood pressure without
detrimental effects on creatinine clearance.36 No
initial dose adjustment is required for patients
with mild-to-moderate renal impairment.
The first evaluation of telmisartan in the
management of renal disease in hypertensive
patients is the Efficacy and Safety in Patients with
Renal Impairment treated with Telmisartan
(ESPRIT) study. This multicentre, open-label study,
conducted in France, Germany and The
Netherlands, was recently completed. It was
performed in patients with three strata of stable
chronic renal impairment (mild-to-moderate
[creatinine clearance 30—74 ml/min per 1.73 m3],
severe renal impairment [creatinine clearance
<30 ml/min per 1.73 m3] or requiring maintenance
haemodialysis) and mild-to-moderate hypertension
(seated diastolic blood pressure 90—109 mmHg).
The treatment was telmisartan 40 or 80 mg given
for 12 weeks and the primary trial end-point was
change in blood pressure. The results of this study
will be available in 2003.
The Diabetics Exposed to Telmisartan
(40/80 mg) And enalaprIL (10/20 mg) (DETAIL)
study37 is a double-blind, double-dummy, multi-
centre study being conducted in Denmark,
Finland, The Netherlands, Norway, Sweden and
the UK. The 252 patients enrolled in DETAIL met
the following criteria: stable serum creatinine for
a minimum of 1 year; urinary albumin excretion
rate of between 11 and 999 µg/min; and
glomerular filtration rate of 70 ml/min per
1.73 m3 or more. The primary outcome of the
study will be a change in glomerular filtration rate
after 5 years. The planned completion date of the
study is 2004.
Nephropathy and cardiovascular disease
Conclusion
Current treatment recommendations to slow the
progression of kidney disease are based on
recognized risk factors, such as high blood
pressure, diabetes mellitus, dyslipidaemia, excess
dietary protein, smoking and RAAS activity. It is
considered advisable to maintain systolic/diastolic
blood pressure at below 130/85 mmHg (or below
125/75 mmHg in patients with proteinuria), to
maintain tight glucose control in patients with
diabetes, to keep the low-density lipoprotein
cholesterol levels at less than 100 mg/dl
(<2.6 mmol/l), to limit the daily intake of protein
to 0.8 g/kg, to abstain from smoking and to
provide ACE inhibitor or ARB treatment.38
Numerous studies indicate that impaired renal
function is an important predictor of
cardiovascular morbidity and mortality. Although
tight blood pressure control can reduce the
incidence of cardiovascular events in patients with
renal disease, it is now evident that blockade of
the RAAS is particularly beneficial in further
reducing these outcomes and in slowing the
progression of renal disease. ACE inhibitors and
ARBs will be important tools for combating these
entities. The possibility that telmisartan may be a
particularly appropriate choice of therapy, based
on its unique pharmacological properties, is
currently being investigated.
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