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  • 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 InternasionalContact:08127101707zulkhair@yahoo.com Medan, 2001

  • Zulkhair Ali

    Div. of Nephrology & HypertensionDept. of Internal Medicine RSMH/ FK UnsriPalembang

    Antihypertensive Drugs and Renal Protection: The Role of ACEI & CCB

  • Can be modifiedCannot be modifiedHypertensionAgeAlbuminuria/ProteinuriaEthnicityDyslipidemiaGenderHemoglobin A1CSmokingAnemiaCaP04

  • Proteinuria (albuminuria) results from injury to glomerular circulationIncreased proteinuria (albuminuria) is associated with progressive kidney disease In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulationProteinuria (albuminuria) is associated with increased cardiovascular risk

  • Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal functionRenal disease is both a cause and consequence of hypertension Reduction of blood pressure reduces cardiovascular risk and renal riskReduction of proteinuria (albuminuria) may lower both cardiovascular risk and renal risk

  • Excess Mortality with Hypertension and Proteinuria in Type 2 DiabetesStatus of hypertension (H) and proteinuria (P) in Type 2 diabetesStandardized Mortality Ratio1,0005000P- H-P- H+P+ H-P+ H+P- H-P- H+P+ H-P+ H+MenWomenWang SL et al., Diabetes Care 1996;19:305-312.

  • With ESRD End Point (%)80100406020048362412Month3.0 g/g1.5
  • ProteinuriaProteinuriaOtherOtherDamageKidney FailureGFRHypertensionHypertensionNational Kidney Foundation. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.

  • Modified from Bakris et al. Am J Kidney Dis. 2000;36:646-661.Systolic Blood Pressure (mm Hg)Trials included: MDRD, RENAAL, IDNT, AIPRI, Captopril Trial, REIN, AASK.130134138142146150154170180r=0.52; P
  • * Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-, CTGF PAI-1 Glomerular capillarypressure Single nephron GFRMacrophageinfiltrationAngiotensin IIMechanical stressMesangial changesOxidative stressProteinuriaNF-B activationGlomerulosclerosisTubulo-interstitial fibrosisRenaldiseaseNephronlosswww.hypertensiononline.orgAngiotensin IACEACEInhibitor

  • Ang IIIncreasedglomerularpressureAng IIUrinary proteinGlucoseAGEsGlycoxidation (glycation)Efferent arteriolarconstriction=angiotensin AT1 receptorwww.hypertensiononline.org

  • TGF-TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitswww.hypertensiononline.org

  • bFGFPDGFAng IITSP1TGF-O2TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitswww.hypertensiononline.org

  • TIMPbFGFPDGFAng IIProteases(-)(-)(+)(+)(+)TSP1ET-1PAI-1O2TGF-TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron unitswww.hypertensiononline.org

  • AIPRI = ACE Inhibition in Progressive Renal Insufficiency StudyREIN = Ramipril Efficacy In Nephropathy StudyMaschio G, et al. N Engl J Med. 1996;334(15):939-945.The GISEN Group. Lancet. 1997;349:1857-1863.

    StudyDrugDosingSurvival BenefitStudy DurationAIPRIBenazepril10-20mg qdP

  • 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

    StudyDrugNDosingStudy yearsEndpointP-valueLewisCaptopril40925 mg tid~ 3Doubling of serum creatinineP=0.007LebovitzEnalapril1655-40 mg qd~ 3Correlation of MAP w/ rate of change in GFRP=0.026ABCD TrialEnalapril4705-40 mg qd524-hr creatinine clearanceNS

  • 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.

    TrialYearEndpoint significanceAchieved BPCaptopril1993P=0.007141/82AIPRI1996P

  • 061218243036100806040200RamiprilPlaceboP=0.02Reprinted from The GISEN Group. Lancet. 1997;349:18571863 with permission from Elsevier.% of patients without combined endpoint**Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure

    Baseline SBP SBPBaseline DBP DBPRamipril149.8-5.8 mmHg92.4-4.2 mmHgPlacebo148.0-3.4 mmHg91.3-3.4 mmHg

  • Intraglomerular pressure descent caused by efferent arteriole dilationSupervised by S Katayama, Professor of Internal Medicine 4, Saitama Medical SchoolDiabetic nephropathyAfferentarterioleEfferentarterioleBowmanscapsuleGlomerulusIntraglomerularpressureImidapril dosageNormalizedintraglomerularpressureAfferentarterioleEfferent arterioleGlomerulusBowmanscapsule

  • Coordinating Investigator Shigehiro Katayama, MDSaitama Medical SchoolStudy Coordinators Ryuichi Kikkawa, MDShiga Univ. of Med. Sci. Syo Isogai, MDToho Univ., Sch. Of Med. Nozomu Sasaki, MDSaitama Medical School Nobuo Matsuura, MDKitasato Univ., Sch. Of Med. Naoko Tajima, MDJikei Univ., Sch. Of Med. Tatsuhiko Uragami, MDNihon Univ., Surugadai Hosp. Yasuko Uchigata, MDTokyo Womens Med Univ. Sch. Of Med.Contoroller Yasuo Ohashi, PhDUniv. 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 withUrinary 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-IDDM Japanese trial of ACE inhibitors on renal protection against nephropathy in IDDMsKatayama S. et al.Diabetes Research and Clinical Practice, 2002

  • Profile of a Randomized Controlled Trial

  • Twenty-two patients were withdrawn from the study. 10 in the placebo, 8 in the captopril and 4 in the imidapril group placeboCaptoprilImidaprilwithdrawal of informed consent23-doubling of serum creatinine211adverse events12-BP elevation1--intercurrent illness or condition212other reasons211

  • Change in Urinary Albumin Excretion95% confidence : p
  • Change in Urinary Albumin Excretion subgroup analysis by basal UAE 95% confidence : p
  • Change in Serum Creatinine LevelmeanSDplacebon=26imidapriln=25captopriln=250.200.150.100.050Change in Serum Creatinine Levelmg/dL0.1300.0510.147final - basalAnalysis of variance

  • subgroup analysis by basal serum creatinine level Change in Serum Creatinine LevelmeanSD : p
  • 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, 2001Calcium Channel Blockers ( CCBs )

  • Proteinuria < 500 mg/day : DHP CCB and Verapamil ACEI

    Proteinuria > 500 mg/day : DHP CCB couldnt reduce proteinuria Non-DHP CCB ACEIKaplan NM, 2004

  • With similar reductions of blood pressureDihydropyridine calcium channel blockers (DHPCCB) increase proteinuriaRef: 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 proteinuriaRef: Smith AC, et al. Kidney Int. 1998;54:889-896.Ref: Kloke H, et al. Kidney Int. 1998; 53:1559-1573.

  • N=173N=121N=111N=723NifedipineOtherDihydropyridineCCBsDiltiazem &VerapamilCCBsAllACE InhibitorsKloke H, et al. Kidney Int. 1998;53:1559-1573.

    Chart1

    -1510

    -10-0.5

    -17-40

    -12-39.6

    MAP(mmHg)

    Albuminuria

    Percent Change

    Sheet1

    NifedipineAll DHPCCBsNon DHPCCBsAll ACE Inhibitors

    MAP(mmHg)-15-10-17-12

    Albuminuria10-0.5-40-39.6

  • DHP vsNDHPRenal 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 proteinuriaThe Role of Hyperte