dr. butar butar - diabetic kidney disease how to regress (pit makasar, 23-26 nov 06)

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    Dr. W. R. Butar-butar Sp.PD

    Subbagian Nefrologi / Hipertensi

    Bagian Pengakit Dalam

    FK Kedokteran UNRI - Riau

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    Penyakit Ginjal Kronik

    Dibuat atas dasar Rumus Kockroft-Gault sebagai berikut :

    (140-umur) X berat badan

    LGF (ml/mnt/1,73m2) *)

    72 X kreatinin plasma (mg/dl)

    *) pada perempuan dikalikan 0,85

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    Klasifikasi Penyakit Ginjal Kronik atas Dasar Derajat Penyakit

    Derajat Penjelasan LFG (ml/mn/1.73m2)

    1 Kerusakan ginjal dengan LFG normal atau 90

    2 Kerusakan ginjal dengan LFG ringan 60 893 Kerusakan ginjal dengan LFG sedang 30 59

    4 Kerusakan ginjal dengan LFG berat 15 29

    5 Gagal ginjal < 15 atau dialisis

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    Penyebab Utama Penykit Ginjal Kronik di Amerika Serikat (1995-1999)

    Penyebab Insiden

    Diabetes melitus 44 %

    - Tipe 1 (7%)

    - Tipe 2 (37%)

    Hipertensi dan penyakit pembuluh darah besar 27 %Glomerulonefritis 10 %

    Nefritis interstitialis 4 %

    Kista dan penyakit bawaan lain 3 %

    Penyakit sistematik (misal, lupus dan vakulitis) 2 %

    Neoplasma 2 %

    Tidak diketahui 4 %

    Penyakit lain 4 %

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    Penyebab Gagal Ginjal yang Menjalani Hemodialisis di Indonesia

    Th. 2000

    Penyebab Insiden

    Glomerulonefritis 49,39 %

    Diabetes melitus 18,65 %

    Obstruksi dan infeksi 12,85 %

    Hipertensi 8,46 %

    Sebab lain 13,65 %

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    10%

    13%

    50%

    27%

    Diabetes Hypertension Glomerulonephritis Other

    The Most Common Cause of ESRD

    Primary Diagnosis for patient

    who start dialysis US Renal Data System. Annual data report 2000

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    Overt proteinuria

    Microalbuminuria

    Glomerular

    hyperfiltation

    Endothelial

    dysfunction

    Risk factors

    Tubulointerstitial

    fibrosis

    Chronic Kidney

    disease

    End Stage

    Kidney Disease

    Hypertension

    Lipid disorders

    Hyperinsulinemia

    Diabetes

    Smoking

    Cardiovascular

    complications

    Kidney Disease Continuum Modified by : Suwitra, 2006

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    What is Diabetic Kidney Disease ?

    Diabetic Kidney Disease (a term often used

    interchangeably with diabetic nephropathy)

    is a chronic, progressive kidney disease that develops

    in about one third of all people with diabetes

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    What is Diabetic Kidney Disease ?

    The signs of Diabetic Kidney Disease are:

    Rising urine albumin and protein excretion

    Rising blood pressure Declining kidney function

    This is associated with:

    A greatly increased risk of cardiovascular disease

    An increased risk of diabetic eye disease (retinopathy)

    An increased risk of diabetic nerve damage (neuropathy)

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    Onset of diabetes 2 5 10 Years 20 30

    Clinical type 2 diabetes

    Functional changes

    Rising blood pressure

    Microalbuminuria

    Structural changes+

    Proteinuria

    Rising serumcreatinine levels

    End-stagerenal disease

    Cardiovascular death

    Natural History of Type 2 Diabetic

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    Normoalbuminuria Sustained

    Normoalbuminuria

    Diabetes duration

    Baseline AERGlycaemic control

    Genetic suspectibility

    Ethnic minorities

    Microalbuminuria Sustained

    microalbuminuria

    Blood pressure

    Glycaemic control

    Intermittent proteinuria

    Proteinuria

    Blood pressure

    End-stage kidney disease

    50%

    30%

    50%30%

    30%

    The stages and determinants of diabetic Kidney Disease

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    METABOLIC HAEMODYNAMIC

    Glucose Flow / pressure

    Vasoactive

    hormones

    (eg II, endothelin)

    PKCIIAdvanced

    glycation

    Cytokines

    TGF VEGFECM

    cross linking ECM

    ECM ACCUMULATION

    Vascular permeability

    PROTEINURIA

    Metabolic and haemodynamic pathogenesis

    of diabetic kidney disease

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    Angiotensin II

    mQ infiltration

    and activationProteinuria TGF-

    And ECM

    PAI-1 Aldosterone

    Pgt

    Endothelial and mesangial

    cell exposure to shear

    stress / stratch

    ECM degradation

    Cytokineproduction

    Inflammation Direct injury to glomerular cells ECM accumulation

    Glomerular and tubule interstitial fibrosis

    Role of angiotensin II in kidney deterioration

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    Angiotensin II is central of the

    pathophysiology of renal disease

    Glomerular pressure injuryOxidative stress

    Inflammation

    Glomerular capillaryhypertension

    Chronic kidney

    disease

    Reduction in

    nephron massGlomerulosclerosis

    Cell and tissue

    growth

    Angiotensin II

    Brewster, Perazella. Am J Med 2004; 116:263-272

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    RENOPROTECTION Reduction of blood pressure

    Reduction of albuminuria

    Non blood pressure dependent action of

    RAAS blockade

    J Am Soc Nephrol 13:S202-S207, 2002

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    Microalbuminuria (MA) is defined as the

    presence of albumin in the urine above the

    normal range of less than 30 milligrams perday butbelow the detectable range with the

    conventional dipstick methodology

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    Category 24 h collection

    (mg/24 h)

    Timed collection

    (g/min)Spot collection

    (g/mg creatinine)Normal 300

    Table testing for proteinuria / albuminuria

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    Local process

    1. Increased intraglomerular capillary pressure

    2. Increased shunting of albumin through glomerular

    membrane pores

    Systemic process

    1. Activation of inflammatory mediators

    2. Increased transcapillary escape rate of albumin

    3. Vascular endothelial dysfunction

    Pathopysiological processes associated with

    microalbuminuria

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    DEVELOPMENT OF MICROALBUMINURIA IN THE DIABETIC PATIENT

    Insulin

    resistance

    Hyperinsulinemia

    NIDDM IDDM

    Intermediate

    metabolites

    Increased

    GFR / RFREfferent

    arteriolar

    involvement

    Leaky

    endothelium

    Modification ofmesangium

    Involvement of

    glomerular

    membrane

    MicroalbuminuriaInvolvement

    of glomerular

    membrane

    Hyperfiltration

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    NO AGEs Insulin resistance

    Oxidant stress

    TG, LDL cholesterolHomocysteinemia

    Endothelial cell

    Hypertension + Microalbuminuria

    Factors that interact to produce and worsen atherosclerosis in

    people with renal disease Bakris, 2004

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    0

    1

    2

    3

    4

    5

    6

    Female Male

    Normoalbuminuria

    Microalbuminuria

    N=2085

    10 year follow up

    Microalbuminuria and ischemic heart disease risk.

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    0

    1

    2

    3

    4

    5

    6

    SBP < 140 SBP 140-166 SBP > 160

    Normoalbuminuria

    Microalbuminuria

    Microalbuminuria and ischemic heart disease (IHD) risk

    associated with blood pressure.

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    0

    0.1

    0.2

    0.3

    0.4

    0.5

    0.6

    0.7

    0.8

    0.9

    1

    1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

    Years of follow-up from baseline

    Su

    rvivalprobability

    None

    Light

    Heavy

    Survival among 3.234 patients with type II diabetes according to proteinuria level

    (WHO multinational study of vascular disease and diabetes)

    J Hyp 2003; 21: 21.1

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    CV Mortality according to Proteinuria in the WESDR study

    Valmadrid CT et al. Arch Intern Med2000; 160:1093-1100

    0

    0.2

    0.4

    0.6

    0.8

    1

    0 2 4 6 8 10 12

    Years of Follow-up

    ProportionSurviving Normoalbuminuria

    Microalbuminuria

    Gross Proteinuria

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    STRATEGIES FORREGRESSING MICROALBUMINURIA

    IN DIABETIC KIDNEY DISEASE

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    ADA GuidelinesInitial Agents of Choice

    Level A evidence

    In the treatment of albuminuria / Kidney Disease

    Type 1 diabetes Type 2 diabetes

    ACE inhibitors ATI receptor antagonist

    If one class is not tolerated, the other should be

    substituted Diabetes Care, Vol 25, suppl 1, January 2002

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    30

    0

    5

    10

    15

    20

    0 3 6 12 18 22 24Follow-up (mo)

    Subjects

    (%)

    Control

    Irbesartan 150 mg

    Irbesartan 300 mg

    Primary Endpoint Analysis in IRMA 2Time to First Occurrence of Clinical Proteinuria

    Parving H-H, et al. N Engl J Med2001;345:870-878.

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    IRMA 2 Primary Endpoint

    Development of Overt Proteinuria

    14.9

    9.7

    5.2

    0

    2

    4

    6

    8

    10

    12

    14

    16

    18

    Control 150 mg 300 mg

    (n=201) (n=195) (n=194)

    Irbesartan

    Subjects

    (%)

    RRR=39%

    p=0.08

    RRR=70%p=0.01

    Parving H-H et al., N Engl J Med2001;345:870-878

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    THE LANCET, Vol 355, January 22, 2000

    Articles

    Heart Outcomes Prevention Evaluation (HOPE) Study Investigators*

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    HOPE study results primary endpoints

    Combined

    cardiovascular

    endpointCardiovascular

    mortality, myocardial

    infarction, stroke

    Cardiovascular

    mortality

    Myocardial

    infarction

    Stroke

    -22%p

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    0

    5

    10

    15

    20

    0 500 1000 1500

    Follow-up (days)

    P

    atientsreachingcomposite

    endpoint[MI,stroke,

    CVdeath](%

    )

    Ramipril

    p < 0.001

    HOPE (ramipril) primary outcomes (I)

    Placebo

    Ramipril and Vasoprotection, Part 2, slide 34

    HOPE Study InvestigatorsNew Engl J Med2000;342:145-153.

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    HOPE/HOPE-TOO: What did happen:Primary outcome

    Hazard

    Years 1 2 3 4 5 6 7

    Ramipril

    Placebo

    0.0

    0.05

    0.10

    0.15

    0.20

    0.25

    0.30

    1 2 3 4 5 6 7

    Ramipril

    Placebo

    ALL: RR: 0.81, CI: (0.74-0.88)

    CONT: RR: 0.83, CI: (0.75-0.91)

    HOPE Study Ends

    Patients who started ACE inhibitor late do not reach the same Risk Reduction comparedto those who started early!

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    0 1 2 3 4.5

    3.0

    2.5

    2.0

    1.5

    1.0

    0.5Meanalbumin/creatininerati

    o

    P=0.001

    P=0.02

    Placebo

    Ramipril

    Time (years)

    Effect of ramipril on degree of albuminuria

    THE LANCET, Vol 355, January 22, 2000

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    MICROHOPE STUDY

    0

    0.04

    0.08

    0.12

    0.16

    0 200 400 600 800 1000 1200 1400 1600 1800

    All-cause mortality

    Placebo

    Ramipiril

    Duration of follow-up (days)

    Kaplan-M

    eierrates

    Kaplan-Meier survival curves for participants with diabetes

    THE LANCET, Vol 355, January 22, 2000

    M h i b hi h ACE i hibiti

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    Mechanisms by which ACE-inhibition

    improves insulin sensitivity

    Henriksen EJ at al, J Cell Physiol 2003

    Bradykinin

    Degradation

    Products

    ACE/Kininase II

    Bradykinin

    Nitric Oxide

    Skeletal MuscleBlood Flow and

    Glucose Metabolism

    Angiotensin I

    Angiotensin II

    Angiotensin II

    ACE Inhibitor

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    ARBs

    Activation Blockade

    Angiotensin

    pathways

    PPARpathways

    Insulinresistance

    Dyslipidemia Cellinflammation

    Cellproliferation

    Hypertension Oxidativestress

    Inhibition of atherosclerosis

    Potention influence of ARBs on pathways that are likely primarily to mediate the anti-

    atherosclerotic effects of peroxisome proliferator activated receptor gamma (PPAR) activationand angiotensin II receptor blockade

    J Hypertension 2004, Vol 22 No. 12

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    Start low-dose sodium diet

    Add a low-dose ACEi or ARB

    Up-titrate ACEi or ARB to max tolerated dose

    Add a diuretic

    Add a low dose of another antiproteinuric agent

    (K5.5 mEq/L

    Add ARB or ACEi

    Up-titrate ARB or ACEi to maximum dose

    Add non-dihyropyridine CCBs (verapamil/di l t iazem)

    Up-titrate non-dihydropyridine CCBS to maximum tolerated dose

    Up-titrate concomitant antihypertensive agents to achieve the maximum

    tolerated blood pressure reduction

    Add a lipid-lowering agent

    Targets of the multidrug approach:

    Blood pressure

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    MicroaIbuminuria in Diabetic Kidney Disease

    An important indicator of risk of renal and

    cardiovascular disease

    A guide to the severity of renal and extrarenal

    manifestation of diabetes mellitus and hypertension

    Strong evidences shown that ACE inhibitor and ARBs

    can regress the progression of diabetic kidney disease

    by regressing the microalbuminuria

    SUMMARY

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