Nefropatia Diabetica: Nuove Proposte Terapeutiche

Nefropatia Diabetica:
Nuove Proposte Terapeutiche
Dr Luigi Gnudi
Reader in Diabetes and Metabolic Medicine
Cardiovascular Division
KCL School of Medicine
Guy’s and St Thomas Hospital
King’s College London
London, UK
Projected prevalent counts of ESRD through 2020
(autoregression model)
Counts projected using forecasting & time series analysis. Original projection uses two models
with data from 1982 through 1997; new projection uses data from 1980 through 2005.
Prevalent counts & adjusted rates
by primary diagnosis
Rates adjusted for
age, gender, & race.
United States Renal Data System. USRDS 2007 Annual Data Report.
Report.
Annual Transition Rates Through Stages of DN
No nephropathy
p
p y
2.0%
(1.9% to 2.2%)
1.4%
(1.3% to 1.5%)
Microalbuminuria
2.8%
2 8%
(2.5% to 3.2%)
3.0%
(2.6%
(2 6% to 3
3.4%)
4%)
Macroalbuminuria
2.3%
(1.5% to 3.0%)
Elevated plasma creatinine or
Renal replacement therapy
DN = diabetic nephropathy.
Adler et al.
al. Kidney Int. 2003;63:225
2003;63:225--232.
4.6%
(3.6% to 5.7%)
19.2%
(14.0%
(14 0% to 24
24.4%)
4%)
Haemodynamic
Metabolic
Glucose
Advanced Glycation
Oxidative stress
Inflammation
Flow/pressure
Renin Angiotensin
I t
Intracellular
ll l signalling
i
lli molecules
l
l
Growth Factors & cytokines
y
Diabetic Glomerulosclerosis
Albuminuria
Stretch
Glucose
Mesangial Cell
PKC
Glut--1
Glut
Glut--1
Glut
P38
TGFβ
TGF
β1
TGFβ
TGF
β1
Fibronectin
Metabolic/ Haemodynamic
y
Insult
Mesangial Cell
AT1R
CYTOKINES
TGF--β1
TGF
VEGF
Ang--2
Ang
TGF--β1
TGF
VEGF
Permeability
Sclerosis
UKPDS: Effect of Tight Glucose Control vs Tight BP
Control on Micro and macrovascular Events
0
Stroke
Any Diabetes
End Point
Microvascular
Outcomes
Death
-10
%
Reduction
-20
*
-30
*
*
-40
-50
*
Tight BP control
(FPG <6 mmol/L)
Tight glucose control
(BP <150/85 mm Hg)
*P < 0.05 compared with tight glucose control.
UK Prospective Diabetes Study Group (UKPDS 38). BMJ. 1998;317:703-713.
Changes in BP and AER by Valsartan and Amlodipine
in T2DM Patients with Microalbuminuria
The MARVAL Study
UAER (µg/min)
Mean BP change (mm Hg)
SBP
DBP
70
0
2
60
4
40
6
30
50
8
-6.6
10
12
p <0.001
-6.5
20
10
-11.2 -11.6
0
V l t
Valsartan
A l di i
Amlodipine
Baseline
Valsartan 24 Wks
Viberti G et al. Circulation 2002; 106: 672–
672–8.
Amlodipine 24 Wks
Glomerular Filtration Barrier
Capillary
Lumen
ENDOTHELIUM
GBM
FP
Urinary
y space
p
Podocyte SlitSlit-Pore
ephrin
Nephrin
Somlo and Mundel Nature Genetics (2000)
Glomerular
G
o e u a Nephrin
ep
Expression
p ess o
Control
Untreated
Diabetic
Di b ti
Diabetic
+Valsartan
Diabetic
+Amlodipine
Davis B. J Hypertens. 2003;21:209
2003;21:209--216.
Anti TGFβ
TGFβ1 Ab as New Targets for Intervention
in Diabetic Nephropathy
C
C TGFβ
TGFβ1 Ab
DM
DM TGFβ
TGFβ1 Ab
Ziyadeh F N et al. (2000) Proc. Natl. Acad. Sci. USA 97, 8015
8015--8020
Inflammation
BG and AER in diabetic rats treated with
mycophenolate
h
l t mofetil
f til (MMF)
○ controls
● DM
■ DM + MMF
Utimura et al. Kidney Int. 2003
Effect of Mycophenolate Mofetil (MMF) on
Glomerulosclerosis Index (A) and Glomerular Macrophage
Density (B) in Diabetic Rats
A
Controls
B
DM
DM + MMF
■ 2 mo
□ 8 mo
Utimura et al. Kidney Int. 2003
Effect of Troglitazone on GFR and AER in
Diabetic Rats
4 wk
12 wk
Isshiki k et al Diabetes 2000
Nephrin Expression in Wild Type and PKCα
PKCα -/- Mice
Diabetes-induced nephrin loss is prevented in the diabetic PKC α -/- mice.
DiabetesParaffin sections; bar=50μ
bar=50μ m.
Menne J et al Kidney Int. 2006; 70: 14561456-1462
PPAR γ agonist and Diabetic Kidney
PPAR-γ
Disease
is there a rationale to date?
-0.5
-1
-1.5
-1.3
a
-2
-2.7
-2.5
a
-3
n
Baseline
RSG
15
8.7 ± 0.4
MET
13
10.4 ± 0.5
0
0
-1
-2
-3
-4
-10
-20
-30
-40
-45
-50
a
-60
-70
-82
-80
a
-90
n
Baseline
RSG
15
195 ± 11
MET
13
232 ± 12
Chang
ge from b
baseline in UACR
R
(μg//mg Cr)
0
Change from
C
f
bas
seline in FPG (mg
g/dl)
Change from baseline in
C
n HbA1c ((%)
Changes in HbA1c, FPG and UACR in Type 2 Diabetes
Patients Treated with RSG or MET after 12 Weeks
-5
-6
-7
-8
-9
-10
n
Baseline
-1.2
NS
-8.7
b
RSG
MET
15
13
16.2 ± 2.8 10.2 ± 1.8
In RSG: Δ FPG vs Δ UACR = r = 0.62; P < 0.01
a P < 0.001 b P < 0.01
Change from baseline to week 12 shown
Adapted from Miyazaki Y, et al. Kidney Int 2007; 72:1367–
72:1367–1373.
ADOPT: Urinary albumin to creatinine ratio
(UACR) over time
13
Rosiglitazone vs metformin
−15.5%
15.5%,, P < 0.001
Rosiglitazone vs glibenclamide
−3.8%
3.8%,, P = NS
UACR
R (µg/mg))
12
Metformin
11
Glibenclamide
10
9
Rosiglitazone
8
7
0
0
1
2
3
4
5
Time (years)
ADOPT Plenary Session. 19th IDF World Diabetes Congress,
Congress, Cape Town, South Africa, December 2006
http://www.adopt--study.org/slides.php (accessed 28.03.2008).
http://www.adopt
Rosiglitazone and Pioglitazone Downregulate the AT1R in
Vascular Smooth Muscle Cells
Modified from A Sugarawa et al., Endocrinology 142: 31253125-3134
Risk of CHF and CV death with TZDs
Risk of CHF
Risk ratio (95% CI)
Weight
Risk ratio (95% CI)
ADOPT (RSG)
12.0%
1.49 (0.62, 3.53)
D
Dargie
i et al.
l (RSG)
7 0%
7.0%
1 81 (0
1.81
(0.55,
55 6
6.02)
02)
Mazzone et al. (Pio
Pio))
1.1%
2.97 (0.12, 72.63)
DREAM (RSG)
5.0%
7.00 (1.59, 30.76)
PPAR ((RSG))
1.2%
2.88 ((0.12,, 69.94))
PROactive (Pio
Pio))
49.0%
1.31 (1.03, 1.67)
RECORD (RSG)
23.5%
2.24 (1.27, 3.96)
TOTAL
100.0%
1.72 (1.21, 2.42)
0.1
0.2
Risk of CV death
0.5
Decreased risk
1
2
5
Increased risk
10
Test for overall effect: p=0.002
Weight
9.8%
Risk ratio (95% CI)
0.83 (0.29, 2.35)
Dargie et al. (RSG)
6.4%
1.30 (0.36, 4.07)
Mazzone et al. (Pio
Pio))
1.4%
0.99 (0.06, 15.75)
DREAM (RSG)
15.2%
1.20 (0.52, 2.77)
PPAR (RSG)
1 9%
1.9%
0
0.48
48 (0
(0.04,
04 5
5.21)
21)
PROactive (Pio
Pio))
20.9%
1.01 (0.50, 2.06)
RECORD (RSG)
44.5%
0.83 (0.51, 1.35)
TOTAL
100.0%
0.93 (0.67, 1.29)
Test for overall effect: p=0.68
Risk ratio (95% CI)
ADOPT (RSG)
0.1
0.2
0.5
Decreased risk
1
2
5
Increased risk
10
Lago RM et al Lancet. 2007
29;370(9593):1129--36
29;370(9593):1129
Effects of PPARγ agonists
in renal collecting duct cells
Effects of PPARγ
PPARγ agonists
ENaC
ENaC translocation
Nucleus
Na+
ENaC
SGK1
ENaC
mRNA
GR
P
PI3 kinase
aldosterone
SGK1
insulin
ENaC = epithelial sodium channel
SGK1 = serum
serum-- and glucocorticoidglucocorticoid-inducible protein kinase 1
GR = glucocorticoid receptor
Hong, G et al. FASEB J 2003; 17:1966–
17:1966–19
1968.
68.
Sites of action of diuretics
HCTZ
SPIRO
FRUS
HCTZ = hydrochlorothiazide
SPIRO = spironolactone
FRUS = furosemide
Adjusted mean ECF at end of study relative to RSG-C in
three diuretic treatment groups and RSG withdrawal group
1.0
RSG withdrawn
Mean ad
djusted ECF
E
diffe
erence
from
m RSGRSG-C (L/1.73m
m2)
RSG + furosemide
RSG + hydrochlorothiazide
0.5
RSG + spironolactone
0
–0.5
05
–1.0
–1.5
–2.0
Error bars = 95% CI
ECF = extracellular fluid
RSG = rosiglitazone
RSG--C = continuation of rosiglitazone
RSG
P = 0.009
Adapted from Karalliedde J, et al. J Am Soc Nephrol 2006; 17:3482–
17:3482–3490.
Proposed Mechanism of Spironolactone Effect
on RSG Induced Fluid Retention
Aldosterone
PPARγγ
PPAR
Insulin
Lumen
Urine
XENaC
Na
Spironolactone
Capillary
Collecting
duct cell
Na
Plasma
volume
expansion
Na + Water
ENaC = epithelial sodium channel
OUT
IN
Vascular Growth Factors
VEGF and Angiopoietins in Vasculogenesis
Anaham D, Science 1997
Angiopietins
Angiopoietins and the kidney
• Human podocytes
express Angiopoietin
Angiopoietin--1
• Tie2 glomerular endothelium/ podocyte
P
Normal physiology
Tie2
Pathophysiology
• Imbalance of Ang1/Ang2 ratio (Ang2>Ang1)
- anti
anti--GBM
- human and experimental diabetes
Angiopoietin-2 and Tie-2 Receptor are
Upregulated in Diabetic Glomerulopathy
Control Angiopoietin 2
Diabetes Angiopoietin 2
Control Tie 2
Diabetes Tie 2
Rizkalla B JASN, 2004
Podocyte Specific Overexpression of AngiopoietinAngiopoietin-2
in Podocin
Podocin--rtTA
rtTA/TRE
/TRE- Transgenic Mice
/TRETetracycline inducible expression system (Tet
(Tet--on)
Podocin promoter
XbaI
EcoR1
rtetR
rtTa
PvuII
Hin
dIII
Vp16
poly A
+ Doxycycline
rtTA
Lac Z
poly A
+/+
Angiopoietin--2
Angiopoietin
TRE/
pminCMV
CON
poly
p
yA
Ang--2
Ang
Actin
ct
B Davis, JASN, 2007
+/-+/
DOX
CON
DOX
Allbuminuria ug
ug// 2
24hr
ge
eometric
c mean x
x/÷
x/
÷ tolera
ance fac
ctor
Podocyte
y Specific
p
Angiopoietin
Angiopoieting p
-2 Overexpression
p
Determines Increase Albuminuria in Transgenic Mice
+/+ CON
100
+/+
/ DOX
*
80
*
+/-- DOX
+/
60
40
20
0
baseline
7
weeks
B Davis, JASN, 2007
+/-- CON
+/
10
* p<0.01
VEGF
A ti VEGF Treatment
Anti
T t
t for
f Intervention
I t
ti
in Diabetic Nephropathy
Anti VEGF Ab
treatment
db/db
-
+
+
-
+
+
VEGF Ab
-
-
+
-
-
+
Flyvberg A et al. (2002) Diabetes 51, 30903090-3094
Thrombotic Microangiopathy in Patients Treated with
Bevacizumab and in mice with Genetic Deletion of VEGF
f
from
Gl
Glomeruli
li
Eremina V et al. N Engl J Med 2008;358:11292008;358:1129-1136
Podocyte Specific Overexpression of sFltsFlt-1
i Podocinin
Podocin
P d i -rtTA/TRE
rtTA/TREtTA/TRE-sFlt
sFltFlt-1 T
Transgenic
i Mice
Mi
(B) Kidney cortex sFlt
sFlt--1 levels
Pod/+
(A) LacZ expression
VEH
Pod/sFlt-1
Pod/sFlt-
DOX
VEH
DOX
sFlt--1
sFlt
~110 kDa
~ 40 kDa
β-actin
sFlt--1/
sFlt
1/β
β-actin
(arbitrarry Units)
1.2
Pod/sFlt-1
Pod/sFltVEH
Pod/sFlt-1
Pod/sFltDOX
*
1
0.8
0.6
0.4
0.2
0
VEH
DOX
Pod/+
VEH
DOX
Pod/sFltPod/sFlt-1
Podocyte
y Specific
p
sFlt-1 Overexpression
sFltp
Ameliorates
Urinary Albumin Excretion in Diabetic Mice
Controls
Diabetic
Album
min excretio
on rate
(μg/24 h)
1000
1000
*#
100
100
10
10
VEH
DOX
0
0
b
6
8
weeks
10
b
6
8
weeks
10
mesangial volume
e fraction
Podocyte Specific sFltsFlt-1 Overexpression Ameliorates
Diabetes--Mediates Mesangial Expansion
Diabetes
0.25
*
0.20
Control VEH
Control DOX
Diabetic VEH
Diabetic DOX
#
0.15
0.10
Control
VEH
Control Diabetic Diabetic
DOX
VEH
DOX
Conclusions
Compounds that target the growth
factor, and inflammatory, responses
in the diabetic kidney
y are likely
y to
preserve microvascular integrity and
provide new opportunities for renal
protection.
The Team
KCL
C UK
GC Viberti
J Karalliedde
G Gruden
G Setti
D Burt
V Rodriguez
A Dei Cas
B Davis
C Ku
C Dessapt
K Price
A Hayward
A McGuigam
University of Newcastle, UK
KE White
S Marshall
R Bilous
NIDDK, NIH, Bethesda, MD, USA
J Kopp
University
y of Miami,, FL,, USA
L Raij
Institute of child health, UCL, UK
D Long, A Woolf
EFSD/Servier