Dr. W. R. Butar-butar Sp.

PD

Subbagian Nefrologi / Hipertensi Bagian Pengakit Dalam FK Kedokteran UNRI - Riau

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

Klasifikasi Penyakit Ginjal Kronik atas Dasar Derajat Penyakit

Derajat 1 2 3 4 5

Penjelasan Kerusakan ginjal dengan LFG normal atau Kerusakan ginjal dengan LFG ringan Kerusakan ginjal dengan LFG sedang Kerusakan ginjal dengan LFG berat Gagal ginjal

LFG (ml/mn/1.73m2) 90 60 89 30 59 15 29 < 15 atau dialisis

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

Penyebab Insiden

Diabetes melitus - Tipe 1 (7%) - Tipe 2 (37%) Hipertensi dan penyakit pembuluh darah besar Glomerulonefritis Nefritis interstitialis Kista dan penyakit bawaan lain Penyakit sistematik (misal, lupus dan vakulitis) Neoplasma Tidak diketahui Penyakit lain

44 %

27 % 10 % 4% 3% 2% 2% 4% 4%

Penyebab Gagal Ginjal yang Menjalani Hemodialisis di Indonesia Th. 2000 Penyebab Insiden

Glomerulonefritis Diabetes melitus Obstruksi dan infeksi Hipertensi Sebab lain

49,39 % 18,65 % 12,85 % 8,46 % 13,65 %

The Most Common Cause of ESRD

27%

13%

10%

50%

Diabetes

Hypertension

Glomerulonephritis

Other

Primary Diagnosis for patient who start dialysis

US Renal Data System. Annual data report 2000

Cardiovascular complications
Microalbuminuria

Overt proteinuria

Glomerular hyperfiltation

Tubulointerstitial fibrosis

Endothelial dysfunction Risk factors Hypertension Lipid disorders Hyperinsulinemia Diabetes Smoking

Chronic Kidney disease

End Stage Kidney Disease

Kidney Disease Continuum

Modified by : Suwitra, 2006

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

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)

Natural History of Type 2 Diabetic

Clinical type 2 diabetes Functional changes Rising blood pressure Microalbuminuria Structural changes+ Proteinuria Rising serum creatinine levels End-stage renal disease Cardiovascular death

Onset of diabetes

10

Years

20

30

50% Normoalbuminuria Diabetes duration Baseline AER Glycaemic control Genetic suspectibility Ethnic minorities 30% Sustained microalbuminuria Sustained Normoalbuminuria

30%

50%

Microalbuminuria 30%

Blood pressure Glycaemic control

Intermittent proteinuria

Proteinuria Blood pressure End-stage kidney disease

The stages and determinants of diabetic Kidney Disease

Metabolic and haemodynamic pathogenesis of diabetic kidney disease

METABOLIC Glucose PKCII Advanced glycation HAEMODYNAMIC Flow / pressure

Vasoactive hormones (eg II, endothelin)

Cytokines TGF VEGF

ECM cross linking ECM Vascular permeability

ECM ACCUMULATION

PROTEINURIA

Role of angiotensin II in kidney deterioration

Angiotensin II mQ infiltration and activation TGF- And ECM

Proteinuria

PAI-1

Aldosterone

Cytokine production

Pgt

Endothelial and mesangial cell exposure to shear stress / stratch

ECM degradation

Inflammation

Direct injury to glomerular cells

ECM accumulation

Glomerular and tubule interstitial fibrosis

Angiotensin II is central of the pathophysiology of renal disease

Glomerular pressure injury Oxidative stress

Inflammation

Angiotensin II
Glomerular capillary hypertension Cell and tissue growth

Chronic kidney disease

Reduction in nephron mass

Glomerulosclerosis

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

RENOPROTECTION Reduction of blood pressure Reduction of albuminuria Non blood pressure dependent action of RAAS blockade

J Am Soc Nephrol 13:S202-S207, 2002

 Microalbuminuria (MA) is defined as the presence of albumin in the urine above the normal range of less than 30 milligrams per

day butbelow the detectable range with the

conventional dipstick methodology

Table testing for proteinuria / albuminuria

Category 24 h collection (mg/24 h) Normal Microalbuminuria Clinical albuminuria <30 30-300 >300 Timed collection (g/min) <20 20-200 >200 Spot collection (g/mg creatinine) <30 30-300 >300

Pathopysiological processes associated with microalbuminuria

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

DEVELOPMENT OF MICROALBUMINURIA IN THE DIABETIC PATIENT Insulin resistance

Hyperinsulinemia

NIDDM

IDDM

Intermediate metabolites

Increased GFR / RFR

Efferent arteriolar involvement

Leaky endothelium

Modification of mesangium

Hyperfiltration
Involvement of glomerular membrane

Involvement of glomerular membrane

Microalbuminuria

Hypertension + Microalbuminuria

NO

AGEs

Insulin resistance TG, LDL cholesterol Oxidant stress

Homocysteinemia

Endothelial cell Factors that interact to produce and worsen atherosclerosis in people with renal disease Bakris, 2004

6
Normoalbuminuria

5 4 3 2 1 0

Microalbuminuria N=2085 10 year follow up

Female

Male

Microalbuminuria and ischemic heart disease risk.

6 5 4 3 2 1 0 SBP < 140 SBP 140-166 SBP > 160

Microalbuminuria Normoalbuminuria

Microalbuminuria and ischemic heart disease (IHD) risk associated with blood pressure.

1 0.9 0.8
Survival probability None Light

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7 8

Heavy

9 10 11 12 13 14 15 16 17

Years of follow-up from baseline

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

CV Mortality according to Proteinuria in the WESDR study

0.8
Proportion Surviving Normoalbuminuria

0.6

Microalbuminuria

0.4

0.2

Gross Proteinuria

10

12

Years of Follow-up
Valmadrid CT et al. Arch Intern Med 2000; 160:1093-1100

STRATEGIES FOR REGRESSING MICROALBUMINURIA IN DIABETIC KIDNEY DISEASE

ADA Guidelines
Initial 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

Primary Endpoint Analysis in IRMA 2

Time to First Occurrence of Clinical Proteinuria

20 15 10 5 0 0

Control Irbesartan 150 mg Irbesartan 300 mg

Subjects (%)

12 Follow-up (mo)

18

22

24

Parving H-H, et al. N Engl J Med 2001;345:870-878.

30

IRMA 2 Primary Endpoint

Development of Overt Proteinuria
RRR=70% p=0.01
14.9

18 16 14 12 10 8 6 4 2 0

RRR=39% p=0.08

Subjects (%)

9.7

5.2

Control (n=201)

150 mg (n=195)

300 mg (n=194)

Irbesartan
Parving H-H et al., N Engl J Med 2001;345:870-878

Articles

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators*

THE LANCET, Vol 355, January 22, 2000

HOPE study results primary endpoints

Combined cardiovascular endpoint
Cardiovascular mortality, myocardial infarction, stroke

Does blood pressure count ?

Cardiovascular mortality Myocardial infarction Stroke

-22% p<0.001

-20% p<0.001 -26% p<0.001 Ramipril n = 4645, Placebo n = 4652

-32% p<0.001

The HOPE Study Investigators, 2000

Ramipril and Vasoprotection, Part 2, slide 34

HOPE (ramipril) primary outcomes (I)

Patients reaching composite endpoint [MI, stroke, CV death] (%)

20

p < 0.001

Placebo

15

10

Ramipril

0 0 500 1000 Follow-up (days) 1500

HOPE Study Investigators New Engl J Med 2000;342:145-153.

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

0.30 Ramipril

HOPE Study Ends

0.25
0.20
Hazard

Placebo

0.15 0.10
ALL: RR: 0.81, CI: (0.74-0.88)

0.05

0.0
Years

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

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

3.0 Mean albumin / creatinine ratio 2.5

Placebo

Ramipril
P=0.02 2.0 1.5 P=0.001 1.0 0.5 0 1 2 Time (years) 3 4.5

Effect of ramipril on degree of albuminuria

THE LANCET, Vol 355, January 22, 2000

MICROHOPE STUDY
0.16

All-cause mortality

Kaplan-Meier rates

0.12

Placebo Ramipiril

0.08

0.04

0 0 200 400 600 800 1000 1200 1400 1600 1800

Duration of follow-up (days) Kaplan-Meier survival curves for participants with diabetes
THE LANCET, Vol 355, January 22, 2000

Mechanisms by which ACE-inhibition improves insulin sensitivity

Angiotensin I Angiotensin II ACE/ Kininase II Bradykinin

Degradation Products

ACE Inhibitor
Angiotensin II Bradykinin

Nitric Oxide Skeletal Muscle Blood Flow and Glucose Metabolism

Henriksen EJ at al, J Cell Physiol 2003

ARBs Activation Blockade

PPAR pathways

Angiotensin pathways

Insulin resistance

Dyslipidemia

Cell inflammation

Cell proliferation

Hypertension

Oxidative stress

Inhibition of atherosclerosis
Potention influence of ARBs on pathways that are likely primarily to mediate the antiatherosclerotic effects of peroxisome proliferator activated receptor gamma (PPAR) activation and angiotensin II receptor blockade
J Hypertension 2004, Vol 22 No. 12

 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 (K<5.5 mEq/L K>5.5 mEq/L

Targets of the multidrug approach: Blood pressure <120/80 mmHg Proteinuria <0.3 g/24 h LDL <100 mg/dL LDL + VLDL <130 mg/dL HbA1c <7.5% (diabetics)

Add ARB or ACEi

Up-titrate ARB or ACEi to maximum dose Add non-dihyropyridine CCBs (verapamil/diltiazem)

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

Algorithm of the remission clinic for chronic nephropathies

(Kid Int, Vol 64 (2003) pp. 1947-1955

SUMMARY
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