Dr. dr. H.

Zulkhair Ali, SpPD-KGH

Tempat/tanggal Lahir:
Air Molek/ 21 April 1961
Pendidikan:
FK Unsri 1987
Peny.Dalam FK Unsri 1996
Pend.Ginjal Hipertensi FKUI 2000
PG Course of Nephrology Australia 2001,2003
Konsultan Ginjal Hipertensi, 2004
S3 Unair 2008
Jabatan:
Staf PDL RSMH/FK Unsri
Organisasi:
Sekretaris PAPDI Cab Sumbagsel
Ketua IKA FK Unsri
Publikasi:
46 makalah Nasional
6 makalah Internasional
Contact:
08127101707
zulkhair@yahoo.com

Medan, 2001

Antihypertensive Drugs
and Renal Protection:
The Role of ACEI & CCB
Zulkhair Ali
Div. of Nephrology & Hypertension
Dept. of Internal Medicine
RSMH/ FK Unsri
Palembang

Can be modified

Cannot be modified

Hypertension

Age

Albuminuria/Proteinuria

Ethnicity

Dyslipidemia

Gender

Hemoglobin A1C
Smoking
Anemia
CaP04

Proteinuria (albuminuria) results from injury

to glomerular circulation
Increased proteinuria (albuminuria) is
associated with progressive kidney disease

In diabetes and hypertension, proteinuria

(albuminuria) is also an indicator of injury in
the systemic circulation
Proteinuria (albuminuria) is associated with
increased cardiovascular risk

Hypertension and proteinuria

(albuminuria) are both independent
variables that predict long-term
decline in renal function

Renal disease is both a cause and

consequence of hypertension
Reduction of blood pressure reduces
cardiovascular risk and renal risk
Reduction of proteinuria (albuminuria) may
lower both cardiovascular risk and renal
risk

Excess Mortality with Hypertension

and Proteinuria in Type 2 Diabetes
1,00
0
Men

Women

Standardized
Mortality Ratio
500

0
PH-

PH+

P+
H-

P+
H+

P- PH- H+

P+
H-

P+
H+

Status of hypertension (H) and proteinuria (P) in Type 2

diabetes
Wang SL et al., Diabetes Care 1996;19:305312.

Baseline Albuminuria

With ESRD End Point (%)

100

HR

80

8.10

3.0 g/g

60

1.5<3.0 g/g

40
20

<1.5 g/g

1.0

0
0

12

24
Month

de Zeeuw et al. Kidney Int. 2004;65:2309-2320.

36

3.23

48

Proteinuria

Damage

Hypertension
Hypertension

Other

Proteinuria

GFR

Hypertension
Hypertension

Kidney
Failure

Other

National Kidney Foundation. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.

Systolic Blood Pressure (mm Hg)

Decline in GFR From Baseline

(mL/min/year)

130
0

134

138

142

146

150

-2
-4
-6
-8

154

170

r=0.52; P<.01
Untreated
HTN

-10
-12

-14
Trials included: MDRD, RENAAL, IDNT, AIPRI, Captopril Trial, REIN, AASK.
Modified from Bakris et al. Am J Kidney Dis. 2000;36:646-661.

180

Mechanical stress
Mesangial changes
Oxidative stress
Proteinuria
NF-B activation
Glomerular capillary
pressure
Single nephron GFR

Angiotensin I

ACE
Inhibitor
ACE

Adhesion molecules
Chemotactic factors
Cell growth
Apoptosis
TGF-, CTGF
PAI-1

Angiotensin II
Macrophage
infiltration

Glomerulosclerosis
Renal
disease

Nephron
loss

Tubulo-interstitial
fibrosis
www.hypertensiononline.org 14

Glucose
Glycoxidatio
n
(glycation)

AGEs

Increased
glomerular
pressure

Ang II

Urinary protein

=angiotensin
AT1 receptor

Efferent
arteriolar
constriction

Ang II

www.hypertensiononline.org

TGF-

TGF- plays a key

role in
extracellular
matrix formation
in mesangium
and interstitium
that leads
to fibrosis and
loss of nephron
units
www.hypertensiononline.org

O2
Ang II

bFGF

PDGF

TSP1

TGF-

O2

TGF- plays a key

role in
extracellular
matrix formation
in mesangium
and interstitium
that leads
to fibrosis and
loss of nephron
units

www.hypertensiononline.org

Proteases
(-)

TIMP

(-)

O2

(+)

PAI-1

Ang II
(+)

(+)
bFGF PDGF

TSP1
ET-1

TGF-

O2

TGF- plays a key

role in
extracellular
matrix formation
in mesangium
and interstitium
that leads
to fibrosis and
loss of nephron
units

www.hypertensiononline.org

Drug

Dosing

Survival
Benefit

AIPRI

Benazepril

10-20
mg qd

P<0.001

~3.0 years

REIN

Ramipril

5-10
mg qd

P=0.03

~ 3.5 years

Study

Study
Duration

AIPRI = ACE Inhibition in Progressive Renal Insufficiency Study

REIN = Ramipril Efficacy In Nephropathy Study

Maschio G, et al. N Engl J Med. 1996;334(15):939945.

The GISEN Group. Lancet. 1997;349:1857-1863.

Study

Lewis

Drug

Captopril

Lebovitz Enalapril

ABCD
Trial

Enalapril

Dosing

409

25 mg tid

165

5-40
mg qd

470

5-40
mg qd

Study
years

Endpoint

P-value

~3

Doubling of
serum
creatinine

P=0.007

~3

Correlation of
MAP w/ rate of
change in GFR

P=0.026

24-hr
creatinine
clearance

NS

ABCD = Appropriate Blood Pressure Control in

Diabetes Trial

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.

Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155.
Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.

Trial

Year

Endpoint
significance

Achieved
BP

Captopril

1993

P=0.007

141/82

AIPRI

1996

P<0.001

139/82

REIN

1997

P=0.03

142/84

RENAAL

2001

P=0.01

142/77

IDNT

2001

P=0.02

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.

Maschio G, et al. N Engl J Med. 1996;334(15):939-945.
The GISEN Group. Lancet. 1997;349:18571863.

% of patients without
combined endpoint*

100
80

Ramipril

60
40

P=0.02

20

Placebo

0
0

12

18

24

30

36

Baseline SBP

SBP

Baseline DBP

DBP

Ramipril

149.8

-5.8 mmHg

92.4

-4.2 mmHg

Placebo

148.0

-3.4 mmHg

91.3

-3.4 mmHg

*Combined endpoint = doubling of baseline serum creatinine concentration

or end stage renal failure
Reprinted from The GISEN Group. Lancet. 1997;349:18571863
with permission from Elsevier.

Intraglomerular pressure descent caused by

efferent arteriole dilation
Diabetic nephropathy
Afferent
arteriole

Efferent
arteriole

Imidapril dosage
Afferent
arteriole

Glomerulus

Glomerulus

Bowmans
capsule

Intraglomerular
pressure

Efferent arteriole

Bowmans
capsule

Normalized
intraglomerular
pressure

Supervised by S Katayama, Professor of Internal Medicine 4, Saitama Medical School

Coordinating Investigator
Shigehiro Katayama, MD

Saitama Medical School

Study Coordinators
Ryuichi Kikkawa, MD

Shiga Univ. of Med. Sci.

Syo Isogai, MD

Toho Univ., Sch. Of Med.

Nozomu Sasaki, MD

Saitama Medical School

Nobuo Matsuura, MD

Kitasato Univ., Sch. Of Med.

Naoko Tajima, MD

Jikei Univ., Sch. Of Med.

Tatsuhiko Uragami, MD

Nihon Univ., Surugadai Hosp.

Yasuko Uchigata, MD

Tokyo Womens Med Univ. Sch. Of Med.

Contoroller
Yasuo Ohashi, PhD

Univ. of Tokyo, Sch. of Health Sci & Nursing

Supported by a grant-in-aid for orphan drug development from

MHW and Research on Health Sciences focusing on Drug
Innovation, Japan Health Sciences

JAPAN-IDDM

Japanese trial of ACE inhibitors on renal protection

against nephropathy in IDDMs

Katayama S. et al. Diabetes Research and Clinical Practice, 2002

Subjects

79 IDDM patients aged 20 to 50 years old associated with

Urinary Albumin Excretion (UAE) 30mg/day
Serum creatinine level 2.0mg/dL
Method

Captopril 12.5mg x 3/day, imidapril 5mg/day or their placebos,

originally planned to include 100pts each into three groups for 3
years (mean 1.48 years) in a double-blind manner.

Profile of a Randomized Controlled Trial

Registered Patients
n = 81
Not Eligible Patients
n=2
Randomization
n = 79

Received Captopril
n = 26

Withdrawn (n = 8)
Withdrawal of informed consent (n = 3)
Doubling of serum creatinine (n = 2)
Others (n = 3)

Completed Trial
n = 18

Received Imidapril
n = 26

Withdrawn (n = 4)
Doubling of serum creatinine (n = 1)
Others (n = 3)

Completed Trial
n = 22

Received Placebo
n= 27

Withdrawn (n = 10)
Withdrawal of informed consent (n = 2)
Doubling of serum creatinine (n = 2)
Others (n = 6)

Completed Trial
n = 17

Twenty-two patients were withdrawn from the study.

10 in the placebo, 8 in the captopril and 4 in the imidapril group
placebo

Captopril

Imidapril

withdrawal of informed consent

doubling of serum creatinine

adverse events

BP elevation

intercurrent illness or condition

other reasons

Change in UAE final basal ratio

Change in Urinary Albumin Excretion

2.5

95% confidence
: p<0.05 vs placebo
: p<0.001 vs placebo

2.0

1.72

1.5

41%

1.0

0.94

0.5

placebo
n=26

0.59

imidapril
n=26

captopril
n=25

Change in UAE final basal ratio

Change in Urinary Albumin Excretion

subgroup analysis by basal UAE
3.5

30 300mg/day

300mg/day

placebo
imidapril
captopril

3.0

95% confidence

2.5
2.0

: p<0.05 vs placebo
: p<0.01 vs placebo
Analysis of variance

1.86
32%

1.61
48%

1.5

1.14

1.0
0.78

0.5
0

0.68

n=12 n=13 n=13

0.52

n=14 n=13 n=12

Change in Serum Creatinine Level

Change in Serum Creatinine Level
final - basal

mg/dL meanSD
0.20 Analysis of variance

0.15

0.147

0.130

0.10

0.051
0.05

placebo
n=26

imidapril
n=25

captopril
n=25

Change in Serum Creatinine Level

subgroup analysis by basal serum creatinine level
Change in Serum Creatinine Level
final basal

mg/dL
0.9

1.0mg/dL

1.0mg/dL

placebo

imidapril

0.77

0.8
0.7

captopril
meanSD

: p<0.05 vs placebo

0.6
0.5
0.4

0.31

0.3
0.2
0.1

0.12

0.17

0.05 0.04

0
n=23 n=22 n=21

n=3
n=3
n=4

The study ended on January 31st, 2,000 on the

recommendation of the independent data safety and
monitoring board (Kazuo Kaizu, Shoji Kawazu,
Yoshitada Yajima, Chikuma Hamada), since a
significant difference between the treated and
placebo group (p=0.007) was obtained.
Fifty-nine patients completed the study.
The average follow-up for these patients was 1.48
years.

SENSOR

The role in decreasing proteinuria is still

controversial

Spesific vasodilator for afferent arteriole

RBF GFR proteinuria
glomerulosclerosis.

Calcium Antagonist / CCBs

Franz H. Messerli :
Not all calcium antagonists are created
equal; therefore, one cannot assume that
all calcium antagonists are equally
dangerous or equally beneficial.

The Calcium antagonists controversy. Am J Cardiol 1998;82:35R-39R

Calcium Channel Blockers ( CCBs )

Dihydropyridine ( DHP )
Nifedipine, Amlodipine, Felodipine
Non-Dihydropyridine ( NDHP )
Diltiazem, Verapamil

OPIE, DRUGS FOR THE HEART, 2001

Proteinuria < 500 mg/day :

DHP CCB and Verapamil ACEI

Proteinuria > 500 mg/day :

DHP CCB couldnt reduce proteinuria
Non-DHP CCB ACEI

Kaplan NM, 2004

With similar reductions of blood pressure

Dihydropyridine calcium channel blockers

(DHPCCB) increase proteinuria
Ref: Mimran A, et al. Diabetes Care. 1988;11:850-853.
Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113:987988.
Ref: Agodoa L, et al. JAMA. 2001;285(21):2719-2728.

Non-DHPCCB reduces proteinuria when a

DHPCCB produces no change or increase in
proteinuria
Ref: Smith AC, et al. Kidney Int. 1998;54:889-896.
Ref: Kloke H, et al. Kidney Int. 1998; 53:1559-1573.

Other
Diltiazem &
Dihydropyridine Verapamil All
Nifedipine CCBs
ACE Inhibitors
CCBs
N=173

N=121

Kloke H, et al. Kidney Int. 1998;53:1559-1573.

N=111

N=723

The general consensus is that the Non-Dihydropyridine CCBs Diltiazem

and Verapamil decrease proteinuria, whereas dihydropyridine CCBs agents
has a minimal or minor effects on proteinuria
The Role of Hypertension on the Progression of Chronic Kidney Diseases

 DILTIAZEM More Than Just Anti-hypertensive

Agent : Organ Protection Effect
CARDIO PROTECTION EFFECT
INTERCEPT STUDY : Diltiazem reduced cardiac events : non-fatal
re-infarction or refractory ischemia, and the need for PTCA / CABG in
acute myocardial infarction ( AMI ).
William E. Boden, et al;, Lancet, 2000, 355: 1751-1756

RENAL PROTECTION EFFECT

Kidney International. 1998 ; 54 : 889-896 : Diltiazem show lower urinary

protein excretion compared to Nifedipine

CEREBRAL PROTECTION EFFECT

NORDIL STUDY : showed Diltiazem group had a 20% lower rate of
all stroke than Diuretics and -Blockers

The Lancet, Vol 356, July 29, 2000

Renal Protection Effect of Diltiazem

Diltiazem reduce Afferent
vasoconstriction

Glomerulus

Bowmans
Capsule

BP

GCP

EAR

Diltiazem reduce Efferent

vasoconstriction

Filtered
Proteins

Effect of Diltiazem & Nifedipine

on Urinary Protein Excretion

1000

mg / day
Nifedipine

600

P < 0.05
Diltiazem

200

Baseline

21 months

Randomized trial in 21 patients type-2 DM with hypertension

Diltiazem O.D. ( mean dose 436 + 43 mg ) and Nifedipine O.D. ( mean dose 78 + 12 mg )
Kidney International. 1998 ; 54: 889-896

Perbandingan efektivitas Diltiazem HCl dan

Imidapril HCl dalam menurunkan
mikroalbuminuria penderita hipertensi

Ferry Usnizar, Zulkhair Ali, Ian Effendi, Ali Ghanie

Bagian Ilmu Penyakit Dalam
Fakultas Kedokteran
Universitas Sriwijaya
2005

Cross-over study
Usia 18-65 tahun
30 pasien hipertensi derajat I dengan
mikroalbuminuria :
kelompok diltiazem HCl kerja panjang
kelompok imidapril HCl

Selama 2 x 4 minggu

Alur penelitian
Diltiazem

Diltiazem

N = 15
Hipertensi stage I
dengan
mikroalbuminuria
N=15

Imidapril
4 mingggu

Imidapril
4 mingggu

CCB non dihidropiridin (Diltiazem HCl)

sama efektif dengan ACE inhibitor
(Imidapril) dalam menurunkan proteinuria
pada pasien hipertensi.

Trandolapril
(5.5 mg/d)

Percent reduction

n=12

Trandolapril (2.9
Verapamil
(315 mg/d) mg/d)
+ Verapamil (219
n=11
mg/d) n=14

-27%
-33%

-62%
*
*p <0.001 combination vs either monotherapy

Bakris GL, et al. Kidney Int. 1998;54:1283-1289.

Reprinted by permission, Blackwell Science, Inc.

Diltiazem & ACE-I Combination

Type 2 Diabetics Microalbuminuria
300

Initial
2 Year Follow-Up

UAE (mg/24 hrs)

250
p < 0.05

200
150
100
50
0
Captopril (n=17)

Captopril + Diltiazem (n=11)

Prez-Maraver M, et al. (EASD) Meeting 2001; Abstract: 1056.

T Tsuge1, A Kurusu1, I Ohsawa1, W Prodjosudjadi2,

Suhardjono2, Dharmeizar2, G Nainggolan2, A Lidya2, RM
Yogiantoro3, Pranawa3, CI Mohani3, D Santoso3, G.
Rizaniansyah3, Y Tomino1
Division of Nephrology, Department of Internal Medicine, Juntendo
University School of Medicine, Tokyo, Japan
2
Nephrology Division, Department of Internal Medicine, Indonesia
University, Jakarta, Indonesia
3
Nephrology Division, Department of Internal Medicine, Airlangga
University, Surabaya, Indonesia
1

Thirty-seven patients were divided into

imidapril monotherapy group and
combination group and were treated for
12 months.

Monotherapy group (n=12):

Imidapril

Combination group (n=25):

Imidapril + Diltiazem

Therapy group

Treatment period

SBP

DBP

UAE

SCr

(No of patients)

(mmHg)

(mmHg)

(g/gCr)

(mg/dL)

14023

8414

1.131.29

1.130.53

12920 *

808

1.672.77

1.120.56

13414 *

8314

0.991.43

1.160.71

14316

8511

0.681.13

1.000.34

13314 *

798 *

0.290.46

1.020.32

13216 *

809 *

0.140.26

1.040.35

14218

8511

0.831.19

1.040.40

13116 *

798 *

0.691.61

1.050.40

13315 *

8111 *

0.400.89 *

1.080.48

Baseline

(n=12)

Imidapril

6 month

monotherapy

(n=12)

12 month

(n=10)

Baseline

(n=25)

Imidapril + CCB

6 month

combination

(n=25)

12 month

(n=22)
Baseline
(n=37)

Total

6 month
(n=37)
12 month
(n=32)

t-test, *: p<0.05 (vs baseline)

Study Conclusions
In monotherapy group:
imidapril significantly reduced SBP at 6 and 12
month,
marginally decreased UAE at 12 month,
did not increase SCr during the study period
In combination group:
imidapril and CCB significantly reduced SBP/DBP at
6 and 12 months compared with that of baseline,
decreased UAE at 6 and 12 month,
did not increase SCr during this period.
.

Hypertension and proteinuria (albuminuria) are both

independent variables that predict long-term decline in
renal function
Renal disease is both a cause and consequence of
hypertension
Reduction of blood pressure reduces cardiovascular and
renal risk
Reduction of proteinuria (albuminuria) may lower both
cardiovascular and renal risk
Imidapril is a unique ACE-inhibitor which has potent BP
lowering, and reno-vascular protection
The use of Non DHP CCBs (diltiazem, verapamil) may be
considered to reduce urinary albumin excretion in
proteinuric hypertensive patients, alone or together with
ACEI.

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