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1
Concepts of Renal Injury & CKD Prevention
Dhavee Sirivongs, M.D.September 15, 2005
Lecture Hall 1Faculty of Medicine, KKU
2
Early Stage CKD has been neglected?
• High compensatory kidneys• No annual check up• Clinical presentation appears at CKD V• Patients are high tolerant • No doctor concern, no GFR calculation• No public awareness• Etc.
3
Concepts
• Critical mass of the kidney
• Genetic factor
• Environmental insults, include. drugs
• In-body factors: Ht
• Progressive nature of kidney disease & kidney
4
CKD: pathophysiology• original insult destroyed most nephron • The rest of nephron was hypertrophy as
compensatory process • Non-immunological insults destroy glomeruli
& tubules• Immunological insults destroy glomeruli &
tubules• Proteinuria destroys the tubule via oxidation• Obstructive nephropathy induces glomerular
and intersitium invasion of wbc
5
Nephron Loss to Critical number
Acute process
Chronic process
Unrecovery ARF
Trauma
Surgical
Immunological (SLE)
Metabolic (DM)
Mechanical (OU)
6
Mechanisms of Renal Injury
• Immunological insults (direct) & proteinuria (indirect): SLE, NS
• Non-immuno insults (direct) & proteinuria (indirect): DM, acetaminophen, pregnancy related
• Obstructive nephropathy (tubular dilatation, jncreased luminal pressure, glomerulosclerosis
7
Collagen type IV
8
Lupus nephritis
9
Lupus nephritis
10
Lupus nephritis
11
Lupus nephritis
12
Obstructive nephropathy
13
14
15
Nephron Loss to Critical number
Wear & Tear
Hemodynamic
Hypertrophy
Fibrotic changes
Etc.
Progressive nephron loss
CKD V
ESRD
Factors: Hypertension, Smoking, Drugs, Pre-renal
16
Markers of renal injury
• Microalbuminuria/Proteinuria
• Urinary sediments: hematuria, pyuria
• Clinical index: Nocturia (poor concentrating ability), Hypertension
• FEMg ?
17
Glomerular hypertension
Renal injury
Reduced number of nephrons
Systemic hypertension
SCARRING
Autoregulation*
* Lost in diabetes
Brenner, Meyer, Hostetter, N Engl J Med, 1982
A unifying hypothesis for the progressive nature of renal disease
18
Proteinuria/Microalbuminuria
The current number one marker for renal injury(also the marker for CVS
morbidity/mortality)
19
Proteinuria Hypertension
20
PODOCYTE DYSFUNCTION IN RESPONSE TO PROTEIN LOAD
Increased glomerular permeability to proteins
ACEi / AIIRA
Podocyte protein accumulation
Proteinuria
Cytoskeleton rearrangement Gene activation
Loss of differentiated phenotype
TGF-
Slit diaphragm dysfunction
Prosclerosing activation of mesangial cells
Podocyte detachment
Foot process effacement
Permselective dysfunction
Permselective dysfunction GLOMERULOSCLEROSIS
Ang II
Abbate et al., Am J Pathol, 2002
21
22
Mechanism of Proteinuria
23
Albuminuria Hypertension
Renal deterioration
Renal InjuryTubular injury Glomerular injury
24
Conclusive concept
Known cause Unknown cause
Treatable cause Diseased kidney
CKD 1
CKD 2
CKD 3
CKD 4
CKD 5
Normal kidney Markers of Kidney damage
25
Life style modification
• Adequate fluid intake
• Low salt diet
• Proper protein diet
• Adequate rest
• Stop smoking
• Exercise
• Etc.
26
Pharmacological approach
Angiotensin converting enzyme inhibitor (ACE-I)
Angiotensin receptor blocker (ARB)
27
Concept of ACE-I/ARB Usage
ใช้�แนวคิด “เศรษฐกิจพอเพ�ยง ลดคิวาม
ฟุ้� �งเฟุ้�อ”
28
REIN: ACE-I IS MORE RENOPROTECTIVE THAN
CONVENTIONAL THERAPY IN NON-DIABETIC RENAL
DISEASE
% of patients without doubling of baseline creatinine or ESRF
60
40
20
00 6 12 18 24 30
80
100
36Follow-up
P=0.02
- 40 –
- 20 –
0 –
20 –
40 –
60 –
% Reduction in
Proteinuria
Diastolic Blood Pressure (mm Hg)
100 –
90 –
80 –
70 –
60 –
Ramipril
Conventional therapy
Gisen group; Lancet 1997
29
3 MONTHS PROTEINURIA REDUCTION PREDICTS LONG-TERM GFR DECLINE The REIN study
Ramipril
Overall
Conventional
* Corrected for GFR
> 3 gr/24 h
GF
R (m
l/min
/mo
nth
)
3 ye
ars
- 20
- 0.6
-0.5
- 0.4
-0.3
- 0.8
- 0.7
- 0.9
-0.20 20 40
proteinuria *( percent change vs .baseline)
3 monthsPerna et al., J Am Soc Nephrol, 2000
30
45
30
25
40
35GF
R(m
l/min
/mon
th)
RamiprilRamipril
GFR = -0.44 ± 0.54
GFR = -0.10 ± 0.50
GFR = -0.81 ± 1.12 GFR = -0.14 ± 0.87
RamiprilConventional
CORE FOLLOW-UP
Ruggenenti et al., Lancet, 1998
31
3 4 5 years-2 - 1 0 1 2
Mogensen et al., 1976* PA 200/120 mmHg
Glo
mer
ular
Filt
ratio
n R
ate
(ml/m
in/1
.73s
qm)
treatment *
GFR 20 ml/year
GFR 2 ml/year40
60
80
100
20
0DYALISIS
32
Decrease in Mean Blood
Pressure (mm Hg)
+ 2 –
0 –
- 2 –
- 4 –
- 6 –
- 8 –
- 9 –
- 10 –
+ 40 –
+ 20 –
0 –
- 20 –
- 40 –
- 60 –
% Reduction in
Proteinuria
p <.001
% with Doubling of
Baseline Creatinine+ ESRD+ death
0
25
50
75
100
0 1 2 3 4
Losartan
Conventional therapy
Brenner et al, N Engl J Med., 2001.
NS
RENAAL: ARB IS BETTER THAN CONVENTIONAL
THERAPY IN TYPE 2 DIABETIC NEPHROPATHY
+ 19
- 45-9.2 -9.6
33
6 MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS RENAL AND CARDIOVASCULAR EVENTSThe RENAAL study
ESRD
CV events
Heart failure
0.4 0.60.2 0.8 1 1.2
RENAAL Study group, 2002
Hazard ratio (95 % C.I.)
Decreased risk Increased risk
34
Prevention of progression and remission strategies for chronic kideny diseases
• Stop activities of the insult(s)
• Save the the rest of nephrons
– Life style modification eg. Stop smoking
– Pharmacological approach, to control hypertension, intraglomerular pressure, protein/microalbuminuria
Ideal drugs: ACEI, ARB
35
ISN: Activities on CKD prevention
• Canada: Symposium on CKD prevention yearly since 2002
• Mexico 2003: The Ensenada Conference on Renal Disease in Minorities Groups, with Emphasis on the Americas
• Italy 2004: Bellago conference: Prevention of Renal Disease in the Emerging World: Toward global Health Equity
• Hong Kong 2004: CKD Prevention• Pre-congress WCN 2005, Singapore
36
ISN: Prevention strategies
• Detecting those at risk of developing CKD• Preventing the onset of CKD in susceptible individuals
by altering lifestyle• Detecting those with early stage CKD• Preventing progression of CKD by intervention• Developing and applying diagnostic guidelines including
albuminuria and estimated GFR as well as therapeutic guidelines
• Raising awareness with the general public, policymakers and physicians
• Creating funds and facilities for global assistances
37
กิ�จกิรรม CKD prevention ในไทย
• คิณะอน�กิรรมกิารป้�องกิ นไตวายเร#$อร ง สมาคิมโรคิไตฯ • แผนงานป้�องกิ นภาวะไตวายแบบบ+รณากิาร• ส มมนาอาย�รแพทย-โรคิไต• แนวป้ฏิบ ตเพ#/อช้ะลอกิารเส#/อมของไต• อบรมวทยากิรพยาบาล• โคิรงกิารศ1กิษาอ ตรากิารเส#/อมของไต• อบรมแพทย-และพยาบาลใน5 พ#$นท�/ใน5 ภาคิ 22-23
กิย . 48
• เผยแพร2คิวามร+ �ให้�กิ บป้ระช้าช้น 5 ธคิ. 48
กิลุ่� มวิ�จ�ยโรคไตเร��อร�ง คณะแพทยศาสตร ม.ขอนแกิ น กิ อต��งต��งแต ปี# พ.ศ . 2544
38
End of the session
39
Loss of Kidney Mass
40
A META-ANALYSIS IN 840 TYPE 1 AND TYPE 2 DIABETIC PATIENTS WITH INCIPIENT AND OVERT NEPHROPATHY AND PRESERVED RENAL FUNCTION
Cha
nge
in p
rote
inur
ia (
%)
Change in GFR (%/year)
Modified from Weidmann et al., Nephrol Dial Transpl, 1995
0
- 20
- 40
- 60
- 80
- 100
+ 20
-20 0-16 -12 -8 -4 +4 +8 +12 +16-100 -50
Nifedipine (n=75)
Diuretics and/or beta-blockers
(n=213)
CCBs, except nifedipine
(n=63)
ACE inhibitors (n=489)
Baseline parameters:
- mean GFR: 83 ml/min
- mean proteinuria: 2.4 g/24 h
41
42
43
Cause/Etiology
Pre-clinical evidences
Clinical evidences
Lab. evidences
44
NEPHRON NUMBER IN 10 MIDDLE-AGED WHITE HYPERTENSIVES AND 10 MATCHED NORMOTENSIVES
Keller et al., N Engl J Med, 2003
Mean glomerular volume (10-3/mm3)
Nephron number per kidney
(x 1
,000
)
HP0
1,000
1,500
2,000
2,500
500
N
6.5 2.8
706 (626-802)
1,429 (1,130-1,627)
*
* p < 0.001
45
HALTING THE PROGRESSION OF CHRONIC NEPHROPATHIES:The negleted issue of residual proteinuria
Lowest< 1.5 g/24 h
Middle1.5 - 3.5 g/24 h
Highest≥3.5 g/24 h
0
0.25
0.50
0.75
1.00G
FR
(m
l/min
/mon
th)
3 ye
ars
Ruggenenti et al., J Am Soc Neph, 2000
Tertiles Proteinuria
Residual proteinuria (6 months)