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Renal Function in
Cardiovascular Disease:
New Understandings
Hypertension: Treatment and control rates
100
Patients treated*
Patients controlled on treatment
to <140/90 mmHg*
Percentage
80
60
40
20
0
1971–1972
1974–1975
*For 1971–1972 and 1974–1975 hypertension
is defined as levels 160/95 mmHg
1976–1980
1988–1991
1991–1994
JNC-V. Arch Intern Med 1993; 153: 154–183
JNC-VI. Arch Intern Med 1997; 157: 2413–2449
Hypertension and end-organ function
Left ventricular
hypertrophy
Coronary heart
disease
Persistently elevated
blood pressure
Stroke
Heart failure
End-stage renal disease
Hypertension and left ventricular hypertrophy
Increase in left ventricular
mass/height (g/m)
15
Male
Female
**
**
10
5
*
0
Presence of hypertension
(160/95 mmHg or on
antihypertensive therapy)
*p<0.05; **p<0.01
Increase in systolic
blood pressure of 20 mmHg
Levy D et al. Ann Intern Med 1989; 110: 101–107
Hypertension and heart failure
Hypertension
Normal
Females
RR=3.0
Males
RR=4.0
0
5
10
15
20
Biennial age-adjusted rate of heart failure
by hypertensive status per 1,000
Kannel WB. Am J Cardiol 1996; 77: 6B–11B
Hypertension, coronary heart disease
and stroke
Relative risk of CHD or stroke
4.00
Stroke
2.00
CHD
1.00
0.50
0.25
76
84
91
98
105
Approximate mean usual diastolic blood pressure (mmHg)
MacMahon S et al. Lancet 1990; 335: 765–774
Hypertension and renal damage
Annual incidence of
hypercreatinemia per 1,000
12
9
6
3
0
90–104
105–114
115
Diastolic blood pressure (mmHg)
Whelton PK et al. J Hypertens 1992; 10(Suppl): S77–S84
Renal impairment: Prevalence
 The progression of renal impairment can lead to
end-stage renal disease which has huge medical,
social and financial consequences
 End-stage renal disease is particularly prevalent in:
– The elderly
– African-Americans
– Patients with diabetes
 Nearly half of the hypertensive population displays
some abnormality of renal function
Progression to end-stage renal disease
In type 1 diabetes, progression to end-stage renal disease
has been sequenced into five stages:
 Early hypertrophy of renal tissue and increased
glomerular filtration rate (GFR)
 Development of glomerular lesions without any clinically
appreciable disease (GFR remains increased)
 Incipient nephropathy with microalbuminuria
(GFR normal or slightly increased)
 Clinical nephropathy with marked proteinuria and
decreased GFR
 GFR continues to decrease and end-stage renal
disease develops
Measurement of GFR as a marker
of renal disease
Endogenous creatinine
Serum
creatinine
Creatinine
clearance
Exogenous markers
Inulin
Radioisotopes
51Cr-EDTA
99Tc-DTPA
125I-iothalamate
Serum creatinine and creatinine clearance:
Normal values
150
Creatinine clearance (ml/min)
Serum creatinine (mg/dl)
2.0
1.5
1.0
0.5
0.0
125
100
Male
Female
Male
Female
Moore MA et al. Am Fam Physician 1992; 45: 1248–1256
Serum creatinine level of 1.4 mg/dl:
What is the renal function?
Serum creatinine (mg/dl)
12
Large muscular male
Normal male
Small female
10
8
6
4
2
0
120
60
GFR (ml/min)
30
15
100
50
25
Fraction of normal renal function (%)
0
Sica DA. Unpublished data
Calculating creatinine clearance
urinary creatinine concentration (mg/dl) x volume (ml)
plasma creatinine concentration (mg/dl) x time (min)
or
140–age (years) x weight (kg) x 0.85 (for women)
72 x serum creatinine (mg/dl)
Cockroft DW et al. Nephron 1976; 16: 31–41
Urinary albumin excretion
Normal excretion
<30 mg/24 hrs (<20 µg/min)
Microalbuminuria
30–300 mg/24 hrs (20–200 µg/min)
Clinical proteinuria
>300 mg/24 hrs (>200 µg/min)
Mogensen CE et al. Lancet 1995; 346: 1080–1084
Microalbuminuria: Prevalence and predictive
power in diabetics
 Type 1 diabetes
– Prevalence: 50%
– Predictive value for the development of
nephropathy: 75%
 Type 2 diabetes
– Prevalence: 25–60% (depending on ethnic origin)
– Predictive value for the development of
nephropathy: 25%
Savage MW et al. Br J Hosp Med 1995; 54: 429–435
Viberti GC et al. In: International Textbook of Diabetic Medicine, 1992
Microalbuminuria: Prevalence and predictive
power in non-diabetics
 Non-diabetics
– Prevalence: 25–40% (depending on level
of antihypertensive control)
– Predictive value for the development of
nephropathy: Thought to be lower than
in diabetic patients
Bigazzi R et al. Nephron 1992; 61: 94–97
Ljungman S. Am J Hypertens 1990; 3: 956–960
Therapeutic options in hypertension
ACE inhibitors
Angiotensin II
antagonists
a1-antagonists
Hypertension
b-blockers
Diuretics
Calcium antagonists
Therapeutic options in heart failure
Heart failure
ACE inhibitors
Indicated in all stages
of symptomatic heart
failure due to systolic
dysfunction,
irrespective of
presence or absence of
signs of volume
overload
Digoxin
Digitoxin
Indicated when a fast
ventricular rate in atrial
fibrillation is present in
any degree of
symptomatic heart
failure due to systolic
dysfunction
Diuretics
Indicated for the
symptomatic
treatment of heart
failure when fluid
overload is present
Task Force of the ESC. Eur Heart J 1997; 18: 736–753
The RAS and ACE inhibition
Angiotensinogen
Renin
Bradykinin
Non-ACE
enzyme
ACE
Inactive kinin
fragments
Serine
peptidase
Angiotensin I
Angiotensin II
ACE inhibitors in hypertension and
heart failure
In hypertension, ACE inhibitors
 Lower blood pressure
 Reduce the progression of end-organ damage
In heart failure, ACE inhibitors
 Improve cardiovascular hemodynamics
 Improve symptomatolgy and exercise capacity
 Decrease morbidity and mortality
Fosinopril improves
symptomatology in heart failure
Placebo
Dyspnea
Fosinopril
Fatigue
Paroxysmal nocturnal
dyspnea
–40
–20
Worsened (%)
0
20
40
60
80
Improved (%)
Brown EJ et al. Am J Cardiol 1995; 75: 596–600
Fosinopril prevents worsening of heart failure
25
Placebo
Event rate (%)
20
Fosinopril
15
10
*
**
5
*
***
0
Supplementary
diuretic
Supplementary
Hospitalization
diuretic or
emergency room visit
Withdrawal
*p=0.002 vs. placebo; **p=0.001 vs. placebo; ***p<0.001 vs. placebo
Erhardt L et al. Eur Heart J 1995; 16: 1892–1899
ACE inhibitors and renal impairment:
Considerations
ACE inhibitors
ACE inhibitors show
renoprotective
effects over and
above blood
pressure control
Dose modifications
are a consideration in
patients with renal
impairment (except
for fosinopril)
Occasional cases of
renal impairment
and hyperkalemia
have been reported
with ACE inhibitors
Adrenergic agents and renal impairment:
Considerations
Adrenergic agents
There is no evidence
of renoprotective
effects over and
above blood
pressure control
Modification of initial
dosing is a
consideration for
hydrophilic
b-blockers
Post-dose temporary
reduction in renal
blood flow and GFR
Calcium antagonists and renal impairment:
Considerations
Calcium antagonists
There is no evidence
of a class-specific
renoprotective effect
over and above
blood pressure
control
The effect of renal
impairment on
metabolism of some
active metabolites of
calcium antagonists
(e.g. diltiazem,
verapamil) is
unknown
Diuretics and renal impairment:
Considerations
Diuretics
There is no evidence
of renoprotective
effects over and
above blood
pressure control
Thiazides may
decrease renal
blood flow and GFR
Efficacy may be
reduced in renal
impairment
Antihypertensive treatment in diabetes:
Additional considerations
Glucose
intolerance
Hyperlipidemia
Insulin
resistance
a1-antagonists
0


ACE inhibitors



b-blockers



0
0/
0
0
0/
0/

0

0

0
Calcium antagonists
Verapamil/diltiazem
Nifedipine
Diuretics
Thiazides
Indapamide
Adapted from Cziraky MJ et al. Ann Pharmacother 1996; 30: 791–801
Fosinopril can improve the lipid profile in
diabetic patients
Change from baseline
7
Placebo
6
Fosinopril
*
5
*
4
*
3
2
1
0
Total
cholesterol
(mmol/l)
*p<0.05 vs. placebo
LDL
cholesterol
(mmol/l)
Plasma
lipoprotein(a)
(mg/dl)
Schlueter WA et al. Am J Cardiol 1993; 72: 37H–44H
Schematic diagram of ACE inhibition
and renal function
Normotensive
Hypertensive
Renal function (%)
Hypertensive treated
with an ACE inhibitor
Time (years)
Renoprotection: ACE inhibitors vs.
other antihypertensives
Calcium antagonists
Diuretics and/or b-blockers
ACE inhibitors
Urinary protein
Mean systemic
blood pressure
0
–10
–20
–30
–40
–50
Decrease from baseline (%)
Böhlen L et al. Am J Hypertens 1994; 7: 84S–92S
ACE inhibitors are renoprotective
ACE inhibitors have demonstrated renoprotective
potential in:
 Patients with type 2 diabetes
 Patients with type 1 diabetes
 Non-diabetic patients with nephropathy
 Non-diabetic patients with hypertension
and nephropathy
 Non-diabetic hypertensive patients
without pre-existing nephropathy
Initial value of
reciprocal creatinine (%)
ACE inhibition: Renoprotection in
type 2 diabetes
Placebo (years 1–5) and
ACE inhibitor (years 6 and 7)
Placebo (years 1–7)
105
ACE inhibitor (years 1–5)
and placebo (years 6 and 7)
ACE inhibitor (years 1–7)
100
95
90
85
80
0
1
2
3
4
Treatment (years)
5
6
7
Ravid M et al. Arch Intern Med 1996; 156: 286–289
ACE inhibition: Renoprotection in
type 1 diabetes
Died or needed dialysis or
transplantation (%)
50
Placebo
Captopril
40
30
20
p=0.006
10
0
0
Placebo
Captopril
n=202
n=207
1
198
207
192
204
2
Follow-up (years)
186
201
171
195
121
140
3
100
103
4
59
64
26
37
Lewis EJ et al. N Engl J Med 1993; 329: 1456–1462
ACE inhibition: Renoprotection in
non-diabetic nephropathy
Patients not reaching
an endpoint (%)
100
90
80
70
Placebo
Benazepril
60
50
0
1
2
3
Treatment (years)
Adapted from Maschio G et al. N Engl J Med 1996; 334: 939–945
ACE inhibition: Renoprotection in
hypertension and nephropathy
Cumulative survival rate (%)
100
90
80
70
Placebo
ACE inhibitor
60
Log rank test p<0.05
50
0
5
10
15
20
Treatment (months)
25
30
35
Hannedouche T et al. Br Med J 1994; 309: 833–837
ACE inhibition: Renoprotection in
hypertensive patients
Time (months)
Decrease in GFR (ml/min/1.73 m2)
0
6
12
18
24
30
36
0
–1
–2
–3
–4
–5
–6
–7
ACE inhibitor
b-blocker
Himmelmann A et al. Am J Hypertens 1996; 9: 850–853
Correlation between beneficial renal
effects and albuminuria
*
Change in GFR
(ml/min/1.73 m2/month)
0.4
Controls
ACE inhibitors
0
–0.4
–0.8
*p=0.02 vs. controls
<30
30–300
Baseline albuminuria (mg/day)
>300
Lebovitz HE et al. Kidney Int 1994; 45(Suppl 45): S150–S155
Dual and compensatory drug elimination
Dual elimination
Dual and compensatory
elimination
Elimination via
the kidney and
liver ONLY
Elimination via the
kidney and liver
PLUS
If function of the kidney
is impaired, excretion
via the liver increases
If function of the liver
is impaired, excretion
via the kidney
increases
Fosinopril: Renal clearance in
patients with renal dysfunction
100
Renal clearance
Hepatic clearance
Clearance (%)
80
60
40
20
0
None*
Mild**
Moderate**
Renal failure
Severe**
*Singhvi SM et al. Br J Clin Pharmacol 1988; 25: 9–16
**Hui KK et al. Clin Pharmacol Ther 1991; 49: 457–467
Accumulation of lisinopril and
enalapril in renal dysfunction
*
**
Fosinoprilat
Enalaprilat
Lisinopril
1.0
1.5
2.0
2.5
3.0
Accumulation index
*p<0.05 vs. enalaprilat
**p<0.001 vs. lisinopril
Sica DA et al. Clin Pharmacokinet 1991; 20: 420–427
Dosing of different ACE inhibitors depending
on renal function
Creatinine clearance (ml/min)
<10
10–30
30–60
>60
2.5 mg/day
5 mg/day
10 mg/day
10 mg/day
Captopril
Reduced
Reduced
12.5 mg
twice/day
12.5 mg
twice/day
Enalapril
2.5 mg every
other day
2.5 mg/day
5 mg/day
5 mg/day
Fosinopril
10 mg/day
10 mg/day
10 mg/day
10 mg/day
Lisinopril
2.5 mg/day
5 mg/day
10 mg/day
10 mg/day
Quinapril
Not determined
2.5 mg/day
5 mg/day
10 mg/day
Ramipril
Not determined 1.25 mg/day 1.25 mg/day 2.5 mg/day
Benazepril
Sica DA. J Cardiovasc Pharmacol 1992; 20(Suppl 10): S13–S20
Simplifying antihypertensive treatment in
the presence of renal failure
If a patient presents with
hypertension
Consider that the patient may
have renal impairment
WHY?
Hypertension accelerates
the decline in GFR and many
hypertensive patients have
some degree of renal
impairment
Measure renal function
If some degree of renal
dysfunction is found, consider
treatment with an ACE inhibitor
If you consider treatment with an
ACE inhibitor, consider dual and
compensatory elimination
WHY?
ACE inhibitors are the only
antihypertensives with
established renoprotective
potential