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1
Nephroprotection:Actual perspective of ACE
inhibitor therapy
Piero RuggenentiMario Negri Institute for Pharmacological Research
Bergamo, Italy
Malaga, October 10, 2005
2
1,800,000 patients with ESRD
J. Weening, G. Remuzzi, Lancet, 2005
3
90 %
4Lysaght, J Am Soc Nephrol, 2002
GLOBAL MAINTENANCE
1990 2000 2010
2,500,000
500,000
1,000,000
1,500,000
2,000,000
0
1,200
600
0$
( bi
llion
s)
1981-1990 1991-2000 2001-2010
800
1,000
$
$
$
400
200
TEN YEAR MEDICAL COSTS
DIALYSIS POPULATION
5
1,000,000 deaths
6
PROGRESSION OF RENAL FAILURE IN 9 DIABETICS
Modified from Jones et al., Lancet, 1979
0
20
40
60
80
0 10 20 30 40 50
Time (months)
1/C
r x
10 3
(µm
ol/l)
7
STRUCTURAL AND FUNCTIONAL ADAPTATION IN RENAL FAILURE
The seconf of two Lumleian Lectures delivered to the Royal College of Physicians of LondonBy Robert Platt, M.D., M.Sc.,F.R.C.P.,
“…the functional disturbances known to occur in human renal disease are precisely those which occur in animal experiment as a result of reduction in the amount of functioning renal substance - that is, loss of nephron”
April 3, 1952 THE BRITISH MEDICAL JOURNAL
8 Zatz et al., J Clin Invest, 1986
Control
Diabetes
P (mmHg)
GLOMERULAR HYPERTENSION AND THE EFECT OF ACE-INHIBITORS IN EXPERIMENTAL DIABETES
0 10 20 30 40 50 60
P = transmembrane pressure difference
70
9 Riser et al., Am J Pathol, 1996
Mechanical strain
Podocyte number
Proteinuria
GLOMERULAR HYPERTENSION
SCARRING
Durvasula et al, Kidney Int, 2004
Ctr0
0.2
0.4
0.6
0.8
1.2
An
g I
I (
pg
pe
r µ
g o
f ce
ll ly
sate
)
1.0*
MS
Pore dimension
Ctr0
0.5
1.0
1.5
2.5
AT
1R
leve
l (a
dju
ste
d f
or
tub
ulin
)
2.0
MS
10
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
11
12
Renal injury
Glomerular-capillary hypertension
Increased filtration of plasma proteins
Excessive tubular reabsorption
Nuclear signals for NF-kB-dependent and independent vasoactive and inflammatory genes. Corresponding protein products then released
into interstitium
Tubular cell transdifferentiation
Fibroblast proliferation
Fibrogenesis
Increased glomerular permeability to macromolecules
Proteinuria
Renal scarring
Reduction of nephron numbers
PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES
Remuzzi and Bertani, N Engl J Med, 1998
13
Time (months after UNx)
Sur
viva
l (%
)
UNx
Control
UNx + Lis
0 3 6 9 1 2 1 50
20
40
60
80
100
ACE INHIBITION PREVENTS RENAL FAILURE AND DEATH IN UNINEPHRECTOMIZED MWF/ZTM RATS
Urin
ary
Pro
tein
Exc
retio
n (
mg
/24
hrs
)
Per
cen
tag
e o
f gl
omer
uli
affe
cted
by
scle
rosi
s
0
20
40
60
80
100
UNxControl UNx + Lis
0
100
200
300
400
500
600
700
UNxControl UNx + Lis
*
**
*
**
* p < 0.05, **p < 0.01 vs controlRemuzzi A. et al., Kidney Int, 1995
14
REIN CORE
Rate of GFR decline according to base-line proteinuria - Interim analysis on 177 patients
STRATUM - 1U. Prot. 1-3 g/24 h
STRATUM - 2U. Prot. ≥ 3 g/24 h
0.5
1.0
0
Rat
e o
f G
FR
dec
line
(m
l/min
/mo
nth
)
p=0.001
0.25±0.08
0.67±0.08
GISEN Group, Lancet, 1997
Conventional
0.89±0.11
Ramipril
0.39±0.100.5
1.0
0
Rat
e o
f G
FR
dec
lin
e(m
l/m
in/m
on
th)
p=0.001
Kidney survival: Conventional 54 %
Ramipril 77 %
15
REIN CORE
GISEN Group, Lancet, 1997
Conventional
Ramipril1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0%
pat
ient
s w
ith d
oubl
ing
of b
ase-
line
crea
tinin
e or
ES
RF
Mea
n ra
te o
f GF
R d
eclin
e (m
l/min
/mon
th) 70
60
50
40
30
20
10
0
3 - 4.5 4.5 - 7 ≥ 7 3 - 4.5 4.5 - 7 ≥ 7
Baseline proteinuria (g/24 h) Baseline proteinuria (g/24 h)
16
70
INCIDENCE OF ESRD IN 352 PATIENTS WITH PROTEINURIC, CHRONIC NEPHROPATHIES ACCORDING TO TREATMENT AND TERTILES OF BASAL GFR Post-hoc analyses of the REIN study
p < 0.05
Ruggenenti et al., J Am Soc Nephrol, 2002
0
40
50
Inci
den
ce o
f E
SR
D (
%)
Lowest(10.5 - 32.6)
Middle(32.6 - 50.8)
Highest(50.8 - 101.0)
60
30
20
10
60.0
40.4
21.4
13.4 10.9
0.0
p < 0.01
Co
nv
enti
on
al
Ra
mip
ril
GFR (ml/min)
TERTILES
17
Patients:
Inclusion criteria:
Treatment:
Follow-up:
OutcomesPrimary: Secondary:
224 subjects with non-diabetic chronic nephropathies
S. creatinine: 3.1- 5.0 mg/dl
Benazepril (20 mg/day) Placebo
3.4 years (mean)
Doubling of s. cretinine, ESRD or deathProteinuria
EFFICACY AND SAFETY OF BENAZEPRIL IN PATIENTS WITH ADVANCED CHRONIC RENAL INSUFFICIENCY (ESBARI) A randomized controlled trial
Hou et al., 2005
18
Pat
ien
ts w
ith
ou
t d
ou
bli
ng
ser
um
cre
atin
ine,
ES
RD
, o
r d
eath
(%
)
Months of follow-up
0 12 24 360
20
40
80
100
Placebo
Benazepril
EFFICACY AND SAFETY OF BENAZEPRIL IN PATIENTS WITH ADVANCED CHRONIC RENAL INSUFFICIENCY (ESBARI) A randomized controlled trial
Hou et al., 2005
60
19
LESS PROGRESSION TO ANURIA IN 60 PERITONEAL DIALYSIS PATIENTS DURING 1-YEAR ACE INHIBITOR THERAPY
A prospective randomized study
Target blood pressure: <135/85 mmHg
0
20
40
60
80
100
Philips et al., J Am Soc Nephrol, 2002
Ramipril(5 mg/day)
Placebo
20
ACE INHIBITORS AND SURVIVAL OF HEMODIALYSIS PATIENTSA retrospective analysis (1994-2000) at a single Institution
Efrati et al., Am J Kidney Dis, 2002
All the benefit driven by a reduced incidence of CV deaths (8 % vs 29 %, p = 0.003) in patients < 65 years-old
Cardioprotection achieved despite less effective BP control
0
20
40
60
80
100
Cum
ulat
ive
surv
ival
(%
)ACEi YES
n = 60
ACEi NOn = 68
p < 0.0006
0 20 40 60 80 100months
21
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
22
0,10 ml/min/month
23
CONTINUED RAMIPRIL
Cohorts ≥ 36 months ≥ 42 months ≥ 48 months ≥ 54 months
G
FR
(m
l/m
in/m
on
th)
0 18 30 0 18 30 42 0 18 30 42 0 18 30 42
-.33 -.30 -.24 -.23 -.20 -.21 -.18 -.16 -.24 -.19 -.17
45
40
35
30
25
20months
GF
R (
ml/
min
/mo
nth
))
45
40
35
30
25
200 18 30 0 18 30 42 0 18 30 42 0 18 30 42 months
-.46 -.52 -.46 -.52 -.49 -.28 -.46 -.45 -.45 -.51 -.53
SWITCHED RAMIPRIL
Ruggenenti et al., J Am Soc Nephrol, 1999
24
G
FR
(m
l/m
in/m
on
th)
CONTINUED RAMIPRIL
Cohorts ≥ 60 months
0 18 30 42 60 months
-.16 -.13 -.11
45
40
35
30
25
20-.10
SWITCHED RAMIPRIL
≥ 60 months
0 18 30 42 60 months
-.25 -.35 -.44 -.30
Ruggenenti et al., J Am Soc Nephrol, 1999
25
16 patients with stable GFR
REMISSION REGRESSION10 patients with increasing GFR
90
80
70
60
50
40
30
20
10
0
months0 10 20 30 40 50 60
GF
R (
ml/m
in/m
on
th)
90
80
70
60
50
40
30
20
10
0
months0 10 20 30 40 50 60
- 31 % - 52 %Change in proteinuria(post- vs pre- breakpoint)
Ruggenenti et al., J Am Soc Nephrol, 1999
Slopes refer to 26 patients on continuated Ramipril treatment since randomization who had at least 6 GFR measurements (≥ 3 on Core and ≤ 3 on Follow-up study)
26
MWF 60 w
0
20
40
60
80
100
0 <25 25-50 50-75 >75 %
MWF 50 w
0
20
40
60
80
100
0 <25 25-50 50-75 >75 %
Num
ber
of
glo
mer
uli
(%)
MWF 60 w + LIS
0
20
40
60
80
100
0 <25 25-50 50-75 >75 %
EVIDENCE FOR GLOMERULAR CAPILLARY REGENERATION AND REABSORPTION OF SCLEROSIS AREAS
Remuzzi et al., J Am Soc Nephrol, 2003
% sclerotic changes
27
#1
#20
#40
#60
#80
#100
#1
#20
#40
#60
#80
#100
#1
#20
#40
#60
#80
#100
MWF 60 W + LISINOPRIL
MWF 60 W
MWF 50 W
28
Ruggenenti et al., THE LANCET • Vol 357 • May 19, 2001
Definitions of progression, remission, and regression of proteinuric chronic nephropathies
Variable Progression Remission Regression
ProteinuriaGlomerular filtration rateRenal structural changes
≥ 1 g/24 hDeclining*Worsening
< 1 g/24 hStableStable
< 0.3 g/24 hIncreasingImproving
*Faster than physiological decline associated with aging (1 ml/min/1.73 sqm per year)
29
g/24
hou
rs
months
0 12 2418
Proteinuria
0
1
2
3
NON-DIABETIC CHRONIC NEPHROPATHIES
6
ml/m
in
0 12 2418
GFR
40
50
60
70
6
months
Ramipril (n = 20)
30
Up-titrate ACE inhibitor dose
Intensify blood pressure control
Combine with other antiproteinuric agents
Vasopeptidase inhibitors
Low-protein diet
protein traffic
- Non-dihydropyridinic Ca-channel blockers- Ang II receptor blockers- Aldosterone antagonists
consequences of protein trafficDrugs targeted to inflammatory or vasoactive genes which are up-regulated by protein reabsorption
- ET-1 receptor antagonists- TGF inhibitors- Lipid lowering agents- C3 inhibitory agents
CAN WE DO BETTER?
31
* No correlation between proteinuria and BP changes
vs
. no
trea
tmen
t (%
)
151050 20-60
-50
-40
-20
-10
0
-30
y=-1.23x - 12.07
24 h Proteinuria*
Ramipril dose (mg/day)
M.A.P.*
151050 20
-30
-20
0
+10
+20
-10
-30
Ramipril dose (mg/day)
r =-1.23; p<0.02
32
Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial
Piero Ruggenenti, Annalisa Perna, Giacomina Loriga, Maria Ganeva, Bogdan Ene-Iordache, Marta Turturro, Maria Lesti, Elena Perticucci, Ivan Nediyalkov Chakarski, Daniela Leonardis, Giovanni Garini, Adalberto Sessa, Carlo Basile, Mirella Alpa, Renzo Scanziani, Gianbattista Sorba, Carmine Zoccali, Giuseppe Remuzzi, for the REIN-2 Study Group*
Lancet 2005; 365: 939-46
33
Patients:
Inclusion criteria:
Treatment:
Follow-up:
Outcomes:
335 subjects with non-diabetic chronic nephropathies
Proteinuria > 1 g/24 hoursCr. Cl. < 70 ml/min/1.73 sqm
Ramipril (2.5-5 mg/day) Target DBP: < 90 mmHg
Ramipril (2.5-5 mg/day) + Felodipine (5 -10 mg/day) Target S/DBP: < 130/80 mmHg
19 (I.Q.R.: 12-35) months
ESRDGFR (in a sub-group)
REIN-2
34
MEAN ARTERIAL PRESSURE IN EACH STUDY ARM
Ruggenenti et al., Lancet, 2005
90
92
94
96
98
100
102
104
Mea
n a
rter
ial
pre
ssu
re(m
mH
g)
Months
0 3 6 9 12 15 18 2421
Ramipril +Felodipine
Ramipril
35
REIN-2
Ruggenenti et al., Lancet, 2005
0
5
10
15
20
25
30
35
40
45
0 6 12 18 24 30 36 42 48 54
Ramipril
Ramipril +
Felodipine
Su
bje
cts
wit
h
ES
RD
(%
)
Follow-up (months)No. at risk
Usual BP
Lower BP
168
167
158
155
121
126
84
88
64
59
50
51
34
43
24
31
13
17
2
0
36
Lancet, 2005
Renoprotective therapy: is it blood pressure or albuminuria that matters?
Paul E. De Jong, Dick de Zeeuw
37
g/24
hou
rs
months
0 12 2418
Proteinuria
0
1
2
3
A CASE-CONTROL STUDY OF SINGLE OR DUAL RAS INHIBITION IN PATIENTS WITH NON-DIABETIC CHRONIC NEPHROPATHIES
6
ml/m
in
0 12 2418
GFR
40
50
60
70
6
months
Ramipril (n = 20)
Benazepril + Valsartan (n = 20)
* ** *
* p < 0.01
38
COOPERATE study: results
Nakao et al., Lancet, 2003
Pa
tient
s w
ithou
t eve
nts
* (%
)
Months after randomisation0 6 12 18 24 30 36
CombinationLosartanTrandolapril
40
80
100
60
20
0
* ESRD and doubling of serum creatinine
39
SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)
Zoja et al., J Am Soc Nephrol, 2002
LisinoprilVehicle Lis + AII-RA Lis + AII-RA+Cerivastatin
Treatment for 10 months (start treatment at 2 months)
Urin
ary
prot
ein
excr
etio
n (
mg/
day)
Control
0
200
400
600
800
*
*
Glo
mer
ulos
cler
osis
(%
)
20
40
60
80
**
*
40
Add non-dihydropyridine CCBs (Verapamil/Diltiazem)
Up-titrate non-dihydropiridine CCBs to max tolerated dose
Up titrate concomitant antihypertensive agents to achieve the maximum tolerated blood pressure reduction
Add a lipid lowering agent
Start low-dose sodium diet
Add low-dose ACE i or AII RA
Up-titrate ACE i or AII RA to max tolerated dose
Add a diuretic
Add a low dose of another antiproteinuric agent
Add AII RA or ACE i
Up-titrate AII RA or ACE i to maximum dose
REMISSION CLINIC
K < 5.5 mEq/l K > 5.5 mEq/l
Ruggenenti et al., Lancet, 2001
41
Targets of the multidrug approach:
Blood pressure < 120/80 mmHgProteinuria < 0.3 g/24 hLDL < 100 mg/dlLDL + VLDL < 130 mg/dlHbA1c < 7.5 % (diabetics)
Ruggenenti et al., Lancet, 2001
REMISSION CLINIC
42
Uri
nar
y pr
ote
in e
xcre
tion
(g
/24
hour
s)
Se
rum cre
atin
ine
(mg/dl)
months
- Full remission of nephrotic syndrome (U.prot. <1g/24 h) in 25 patients - Stable s. creatinine
0 6 12 18 24 24 - 500
1
2
3
4
5
- 12
Remission clinic
0
2
4
6
8
- 6
43
Uri
nar
y pr
ote
in e
xcre
tion
(g
/24
hour
s)
Se
rum cre
atin
ine
(mg/dl)
months
0 6 12 18 24 > 240
1
2
3
4
5
- 12
Remission clinic
0
2
4
6
8
- 6
- Residual proteinuria > 1g/24 h in 11 patients
*
* 2 patients progressed to ESRD
44
Uri
nar
y pr
ote
in e
xcre
tion
(g
/24
hour
s)S
erum
crea
tinin
e(m
g/dl)
months
FULL-RESPONDERS (n=5)
- Full remission of nephrotic syndrome (U.prot. <1g/24 h) - Stable s. creatinine
0 6 12 18 24 > 240
1
2
3Remission clinic
0
2
4
6
8
- 6
TYPE 2 DIABETES
45
Uri
nar
y pr
ote
in e
xcre
tion
(g
/24
hour
s)S
erum
crea
tinin
e(m
g/dl)
months
0 6 12 18 24 > 240
1
2
3Remission clinic
0
2
4
6
8
- 6
TYPE 2 DIABETES
PARTIAL-RESPONDERS (n=13)
- Residual proteinuria > 1g/24 h
46
(m
mH
g)
120
140
160
180
200
60
80
100
TYPE 2 DIABETES
40
0 6 12 18 24 > 24- 6
SBP
Responder
Non-Responder
ResponderNon-Responder
Remission clinic
47
Non-diabetic proteinuric nephropathies
Num
ber
0
10
25
RespondersNon-
responders
15
5
p < 0.01 non-diabetic proteinuric nephropathy vs diabetic nephropathy (Chi square test)
Diabetic nephropathy
20
Num
ber
0
10
25
RespondersNon-
responders
15
5
20
25
11
5
13
48
SWIMMING TO REDUCE PROTEINURIA?
Pechter et al., Nephrol Dial Transplant, 2003
20 patients: proteinuric chronic nephropathyTreatments: 12-week regular acquatic exercise
Blood pressure Proteinuria
p = 0.005
1.0
0.5
1.5
g /
24h
1.0+0.3
0.5+.03
Pre PostPre Post
mm
Hg
150
140
130
120
100
90
80
70
p < 0.01
p < 0.05
49
A swimming pool for the Clinical Research Center?