dr. butar butar - diabetic kidney disease how to regress (pit makasar, 23-26 nov 06)
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7/30/2019 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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