Dr.Dr. dr. dr. H. Zulkhair Ali, SpPD-KGH H. Zulkhair Ali, SpPD-KGH
Tempat/tanggal Lahir:Tempat/tanggal Lahir: Air Molek/ 21 April 1961Air Molek/ 21 April 1961
Pendidikan:Pendidikan: FK Unsri 1987FK Unsri 1987
Peny.Dalam FK Unsri 1996Peny.Dalam FK Unsri 1996Pend.Ginjal Hipertensi FKUI 2000Pend.Ginjal Hipertensi FKUI 2000
PG Course of Nephrology Australia 2001,2003PG Course of Nephrology Australia 2001,2003Konsultan Ginjal Hipertensi, 2004Konsultan Ginjal Hipertensi, 2004
S3S3 Unair 200 Unair 20088Jabatan:Jabatan:
Staf PDL RSMH/FK UnsriStaf PDL RSMH/FK UnsriOrganisasi:Organisasi:
Sekretaris PAPDI CabSekretaris PAPDI Cab Sumbagsel Sumbagsel Ketua IKetua IKA FK Unsri KA FK Unsri
Publikasi:Publikasi: 446 makalah Nasional6 makalah Nasional
66 makalah Internasional makalah InternasionalContact:Contact:
[email protected]@yahoo.com Medan, 2001
Zulkhair AliZulkhair Ali
DivDiv. of . of Nephrology & HypertensionNephrology & HypertensionDept. of Internal Medicine Dept. of Internal Medicine
RSMH/ FK UnsriRSMH/ FK UnsriPalembangPalembang
Antihypertensive Drugs Antihypertensive Drugs and Renal Protection: and Renal Protection: The Role of The Role of ACEIACEI & & CCBCCB
Can be modified Cannot be modified
Hypertension AgeAlbuminuria/Proteinuria Ethnicity
Dyslipidemia GenderHemoglobin A1C
SmokingAnemiaCa•P04
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 Excess Mortality with Hypertension and Proteinuria in Type 2 Diabetesand Proteinuria in Type 2 Diabetes
Status of hypertension (H) and proteinuria (P) in Type 2 Status of hypertension (H) and proteinuria (P) in Type 2 diabetesdiabetes
Standardized Standardized Mortality RatioMortality Ratio
1,001,0000
500500
00P- P- H-H-
P- P- H+H+
P+ P+ H-H-
P+ P+ H+H+
P- P- H-H-
P- P- H+H+
P+ P+ H-H-
P+ P+ H+H+
MenMen WomenWomen
Wang SL Wang SL et al.et al., , Diabetes CareDiabetes Care 1996;19:305- 1996;19:305-312.312.
With
ESR
D E
nd P
oint
(%)
With
ESR
D E
nd P
oint
(%) 8080
100100
4040
6060
2020
004848363624241212
Month
3.0 g/g3.0 g/g
1.5<3.0 g/g1.5<3.0 g/g
<1.5 g/g<1.5 g/g
HRHR
8.108.10
3.233.23
1.01.0
00
Baseline AlbuminuriaBaseline Albuminuria
de Zeeuw et al. de Zeeuw et al. Kidney Int.Kidney Int. 2004;65:2309-2320. 2004;65:2309-2320.
ProteinuriaProteinuria ProteinuriaProteinuria
OtherOther OtheOtherr
DamageDamage KidneyKidneyFailureFailureGFRGFRHypertensionHypertension HypertensionHypertension
National Kidney Foundation. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.
Modified from Bakris et al. Modified from Bakris et al. Am J Kidney DisAm J Kidney Dis. 2000;36:646-661.. 2000;36:646-661.
Systolic Blood Pressure (mm Hg)Systolic Blood Pressure (mm Hg)
Trials included: MDRD, RENAAL, IDNT, AIPRI, Captopril Trial, REIN, AASK.Trials included: MDRD, RENAAL, IDNT, AIPRI, Captopril Trial, REIN, AASK.
130130 134134 138138 142142 146146 150150 154154 170170 180180
r=0.52; r=0.52; PP<.01<.01
Dec
line
in G
FR F
rom
Bas
elin
eD
eclin
e in
GFR
Fro
m B
asel
ine
(mL/
min
/yea
r)
(mL/
min
/yea
r) UntreatedUntreated
HTNHTN
00
-2-2
-4-4
-6-6
-8-8
-10-10
-12-12
-14-14
14
Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-, CTGF PAI-1
Glomerular capillarypressure
Single nephron GFR
Macrophageinfiltration
Angiotensin II
Mechanical stressMesangial changesOxidative stressProteinuriaNF-B activation
Glomerulosclerosis
Tubulo-interstitial
fibrosis
Renaldisease
Nephronloss
www.hypertensiononline.org
Angiotensin I
ACEACE
Inhibitor
Ang II
Increasedglomerularpressure
Ang II
Urinary proteinGlucose
AGEsGlycoxidation (glycation)
Efferent arteriolarconstriction
=angiotensin AT1 receptor
www.hypertensiononline.org
TGF-
TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units
www.hypertensiononline.org
bFGF PDGF
Ang II
TSP1
TGF-
O2•
TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units
O2•
www.hypertensiononline.org
TIMP
bFGF PDGF
Ang II
Proteases
(-)
(-)
(+)
(+)
(+)
TSP1
ET-1
PAI-1
O2•
TGF-
TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units
O2•
www.hypertensiononline.org
Study Drug Dosing Survival Benefit
Study Duration
AIPRI Benazepril 10-20mg qd P<0.001 ~3.0 years
REIN Ramipril 5-10 mg qd P=0.03 ~ 3.5 years
AIPRI = ACE Inhibition in Progressive Renal Insufficiency StudyREIN = Ramipril Efficacy In Nephropathy Study
Maschio G, et al. N Engl J Med. 1996;334(15):939-945.The GISEN Group. Lancet. 1997;349:1857-1863.
Study Drug N Dosing Study years Endpoint P-value
Lewis Captopril 409 25 mg tid ~ 3
Doubling of serum
creatinineP=0.007
Lebovitz Enalapril 165 5-40 mg qd ~ 3
Correlation of MAP w/ rate of change in GFR
P=0.026
ABCD Trial Enalapril 470 5-40
mg qd 5 24-hr creatinine clearance NS
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.
ABCD = Appropriate Blood Pressure Control in Diabetes Trial
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;349:1857–1863.
Baseline SBP ∆ SBP Baseline DBP ∆ DBPRamipril 149.8 -5.8 mmHg 92.4 -4.2 mmHgPlacebo 148.0 -3.4 mmHg 91.3 -3.4 mmHg
0 6 12 18 24 30 36
10080604020
0
Ramipril
Placebo
P=0.02
Reprinted from The GISEN Group. Lancet. 1997;349:1857–1863 with permission from Elsevier.
% o
f pat
ient
s with
out
com
bine
d en
dpoi
nt*
*Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure
Intraglomerular pressure descent caused by Intraglomerular pressure descent caused by efferent arteriole dilationefferent arteriole dilation
Supervised by S Katayama, Professor of Internal Medicine 4, Saitama Medical School
Diabetic nephropathyAfferentarteriole
Efferentarteriole
Bowman’scapsule
Glomerulus
Intraglomerularpressure
Imidapril dosage
Normalizedintraglomerularpressure
Afferentarteriole Efferent arteriole
Glomerulus
Bowman’scapsule
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 Women’s 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
●Subjects79 IDDM patients aged 20 to 50 years old associated with
Urinary Albumin Excretion (UAE) ≧ 30mg/daySerum creatinine level ≦ 2.0mg/dL
●MethodCaptopril 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.
JAPAN-IDDMJapanese trial of ACE inhibitors on renal protection against nephropathy in IDDMs
Katayama S. et al. : Diabetes Research and Clinical Practice, 2002
Profile of a Randomized Controlled TrialProfile of a Randomized Controlled TrialRegistered Patientsn = 81
Randomizationn = 79
Received Placebon= 27
Received Captopriln = 26
Withdrawn (n = 8)Withdrawal of informed consent (n = 3)Doubling of serum creatinine (n = 2)Others (n = 3)
Completed Trial
Not Eligible Patientsn = 2
n = 18
Received Imidapriln = 26
Completed Trial Completed Trial n = 22 n = 17
Withdrawn (n = 4)Doubling of serum creatinine (n = 1)Others (n = 3)
Withdrawn (n = 10)Withdrawal of informed consent (n = 2)Doubling of serum creatinine (n = 2)Others (n = 6)
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 2 3 -
doubling of serum creatinine 2 1 1
adverse events 1 2 -
BP elevation 1 - -
intercurrent illness or condition 2 1 2
other reasons 2 1 1
Change in Urinary Albumin ExcretionChange in Urinary Albumin Excretion95% confidence : p<0.05 ( vs placebo ) : p<0.001 ( vs placebo )
placebo( n=26 )
imidapril( n=26 )
captopril( n=25 )
2.5
2.0
1.5
1.0
0.5
0
1.72
0.59
0.94
Chan
ge in
UAE
(fin
al/
basa
l ra
tio)
41%
Change in Urinary Albumin ExcretionChange in Urinary Albumin Excretionー subgroup analysis by basal UAE ー
95% confidence : p<0.05 ( vs placebo ) : p<0.01 ( vs placebo )
3.5
3.0
2.0
1.0
0.5
0( n=12 )( n=13 )( n=13 )
2.5
1.5
( n=14 )( n=13 )( n=12 )
30 ~ 300mg/day > 300mg/day
placeboimidaprilcaptopril
1.86
0.680.78
1.61
0.52
1.14
Chan
ge in
UAE
(fin
al/
basa
l ra
tio)
Analysis of variance
32%48%
Change in Serum Creatinine LevelChange in Serum Creatinine LevelmeanSD
placebo( n=26 )
imidapril( n=25 )
captopril( n=25 )
0.20
0.15
0.10
0.05
0Chan
ge in
Ser
um C
reat
inin
e Le
vel
( mg/dL )
0.130
0.051
0.147
(fin
al -
basa
l)Analysis of variance
ー subgroup analysis by basal serum creatinine level ー
Change in Serum Creatinine LevelChange in Serum Creatinine Level
meanSD : p<0.05 ( vs placebo )
0.90.8
0.4
0.10
( n=23 )( n=22 )( n=21 )
0.6
0.2
( n=3 )( n=3 )( n=4 )
< 1.0mg/dL ≧1.0mg/dL placeboimidaprilcaptopril
0.5
0.7
0.3
( mg/dL )
0.05 0.040.12
0.77
0.17
0.31
Chan
ge in
Ser
um C
reat
inin
e Le
vel
(fin
al -
basa
l)
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
• Dihydropyridine ( DHP ) Nifedipine, Amlodipine, Felodipine
• Non-Dihydropyridine ( NDHP ) Diltiazem, Verapamil
OPIE, DRUGS FOR THE HEART, 2001
Calcium Channel Blockers ( CCBs )
Proteinuria < 500 mg/day : DHP CCB and Verapamil ACEI
Proteinuria > 500 mg/day : DHP CCB couldn’t reduce proteinuria Non-DHP CCB ACEI
Kaplan NM, 2004Kaplan 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;113:987-
988.− 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.
N=173 N=121 N=111 N=723
NifedipineOtherDihydropyridineCCBs
Diltiazem &VerapamilCCBs
AllACE Inhibitors
Kloke H, et al. Kidney Int. 1998;53:1559-1573.
DHP vs NDHPRenal EffectsCapillary Glomerular PressureProteinuria
Cardiac EffectsReflex Sympathetic ActivityRisk-Ratio of Ischemia
Cerebral EffectsIntracranial Pressure
Ca-Antagonists Differs in Clinical Practice
Epstein M, 1991, Bakris GL, 1993, Mancia G, 1996, Messerly FH, 1996
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
• CARDIO PROTECTION EFFECTINTERCEPT 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 EFFECTKidney International. 1998 ; 54 : 889-896 : Diltiazem show lower urinary protein excretion compared to Nifedipine
• CEREBRAL PROTECTION EFFECTNORDIL STUDY : showed Diltiazem group had a 20% lower rate of all stroke than Diuretics and -Blockers
The Lancet, Vol 356, July 29, 2000
“ “ DILTIAZEMDILTIAZEM “ More Than Just Anti-hypertensive “ More Than Just Anti-hypertensive Agent : Organ Protection Effect “ Agent : Organ Protection Effect “
EAR
FilteredProteins
Bowman’sCapsule
GlomerulusDiltiazem reduce Afferentvasoconstriction
BP
GCP
Diltiazem reduce Efferentvasoconstriction
Renal Protection Effect of DiltiazemRenal Protection Effect of Diltiazem
Randomized trial in 21 patients type-2 DM with hypertensionDiltiazem O.D. ( mean dose 436 + 43 mg ) and Nifedipine O.D. ( mean dose 78 + 12 mg )
Kidney International. 1998 ; 54: 889-896
Effect of Diltiazem & Nifedipine Effect of Diltiazem & Nifedipine on Urinary Protein Excretion on Urinary Protein Excretion
mg / day
Nifedipine
600P < 0.05
Baseline
Diltiazem
200
1000
21 months
Perbandingan efektivitas Diltiazem HCl dan Perbandingan efektivitas Diltiazem HCl dan Imidapril HCl dalam menurunkan Imidapril HCl dalam menurunkan
mikroalbuminuria penderita hipertensimikroalbuminuria 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 penelitianAlur penelitian
N = N = 1515
Hipertensi stage I Hipertensi stage I dengandenganmimikkroalbuminuriaroalbuminuria
N=N=1515
Diltiazem
Imidapril
Diltiazem
Imidapril4 mingggu 4 mingggu
CCB non dihidropiridin (Diltiazem HCl) sama efektif dengan ACE inhibitor (Imidapril) dalam menurunkan proteinuria pada pasien hipertensi.
Trandolapril (5.5 mg/d)
Verapamil (315 mg/d)
Trandolapril (2.9 mg/d) + Verapamil (219 mg/d)
*
Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc.
-33%-27%
-62%
*p <0.001 combination vs either monotherapy
Perc
ent
redu
ctio
n
n=12 n=11 n=14
Diltiazem & ACE-I CombinationType 2 Diabetics –Microalbuminuria
Pèrez-Maraver M, et al. (EASD) Meeting 2001; Abstract: 1056.
0
50
100
150
200
250
300
Captopril (n=17) Captopril + Diltiazem (n=11)
UAE
(mg/
24 h
rs)
Initial 2 Year Follow-Up
p < 0.05
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
1Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan2Nephrology Division, Department of Internal Medicine, Indonesia University, Jakarta, Indonesia3Nephrology Division, Department of Internal Medicine, Airlangga University, Surabaya, Indonesia
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 groupTreatment period SBP DBP UAE SCr
(No of patients) (mmHg) (mmHg) (g/gCr) (mg/dL)
Baseline140±23 84±14 1.13±1.29 1.13±0.53
(n=12)
Imidapril 6 month129±20* 80±8 1.67±2.77 1.12±0.56
monotherapy (n=12)
12 month134±14* 83±14 0.99±1.43 1.16±0.71
(n=10)
Baseline143±16 85±11 0.68±1.13 1.00±0.34
(n=25)
Imidapril + CCB 6 month133±14* 79±8* 0.29±0.46 1.02±0.32
combination (n=25)
12 month132±16* 80±9* 0.14±0.26 1.04±0.35
(n=22)
Total
Baseline142±18 85±11 0.83±1.19 1.04±0.40
(n=37)
6 month131±16* 79±8* 0.69±1.61 1.05±0.40
(n=37)
12 month133±15* 81±11* 0.40±0.89* 1.08±0.48
(n=32)
t-test, *: p<0.05 (vs baseline)
SStudy Conclusionstudy ConclusionsIn 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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