Transcript Nessun titolo diapositiva

Nephroprotection:
Actual perspective of ACE
inhibitor therapy
Piero Ruggenenti
Mario Negri Institute for Pharmacological Research
Bergamo, Italy
Malaga, October 10, 2005
1
1,800,000 patients with ESRD
2
J. Weening, G. Remuzzi, Lancet, 2005
90 %
3
DIALYSIS POPULATION
GLOBAL MAINTENANCE
TEN YEAR MEDICAL COSTS
1,200
2,000,000
1,000
$ ( billions)
2,500,000
1,500,000
800
600
1,000,000
400
500,000
200
0
1990
4
0
2000
2010
1981-1990
1991-2000
2001-2010
Lysaght, J Am Soc Nephrol, 2002
1,000,000 deaths
5
PROGRESSION OF RENAL FAILURE IN 9 DIABETICS
1/Cr x 10 3 (µmol/l)
80
60
40
20
0
0
10
20
30
40
50
Time (months)
6
Modified from Jones et al., Lancet, 1979
April 3, 1952
THE BRITISH MEDICAL JOURNAL
STRUCTURAL AND FUNCTIONAL
ADAPTATION IN RENAL FAILURE
The seconf of two Lumleian Lectures delivered to the Royal College of Physicians of London
By 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”
7
GLOMERULAR HYPERTENSION AND THE EFECT OF ACEINHIBITORS IN EXPERIMENTAL DIABETES
Control
Diabetes
0
10
20
30
40
50
60
70
DP (mmHg)
DP = transmembrane pressure difference
8
Zatz et al., J Clin Invest, 1986
GLOMERULAR HYPERTENSION
1.2
2.5
*
AT1R level
(adjusted for tubulin)
Podocyte number
Ang II
(pg per µg of cell lysate)
Mechanical strain
1.0
0.8
0.6
0.4
0.2
0
2.0
1.5
1.0
0.5
0
Ctr
MS
Ctr
MS
Durvasula et al, Kidney Int, 2004
Pore dimension
Proteinuria
SCARRING
9
Riser et al., Am J Pathol, 1996
PODOCYTE DYSFUNCTION IN RESPONSE TO PROTEIN LOAD
Ang II
ACEi / AIIRA
Increased glomerular permeability
to proteins
Proteinuria
Podocyte protein accumulation
Cytoskeleton
rearrangement
Gene activation
Loss of differentiated
phenotype
TGF-b
10
Slit diaphragm
dysfunction
Prosclerosing activation
of mesangial cells
Permselective
dysfunction
GLOMERULOSCLEROSIS
Podocyte
detachment
Foot process
effacement
Permselective
dysfunction
Abbate et al., Am J Pathol, 2002
11
PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES
Renal injury
Reduction of
nephron numbers
Glomerular-capillary
hypertension
Increased glomerular
permeability to macromolecules
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
Renal scarring
Remuzzi
and Bertani, N Engl J Med, 1998
12
Proteinuria
IN
(mg/24 hrs)
600
500
400
300
200
100
0
**
Control
UNx
UNx + Lis
*
100
Control
UNx + Lis
100
Survival (%)
80
60
40
20
**
80
60
40
20
UNx
0
0
Control
13
DEATH
*
700
Percentage of glomeruli
affected by sclerosis
Urinary Protein Excretion
ACE INHIBITION PREVENTS RENAL FAILURE AND
UNINEPHRECTOMIZED MWF/ZTM RATS
* p < 0.05, **p < 0.01 vs control
UNx
UNx +
Lis
0
3
6
9
12
15
Time (months after UNx)
Remuzzi A. et al., Kidney Int, 1995
REIN CORE
Rate of GFR decline according to base-line proteinuria
- Interim analysis on 177 patients
p=0.001
1.0
0.67±0.08
0.5
0.25±0.08
(ml/min/month)
1.0
Rate of GFR decline
(ml/min/month)
Rate of GFR decline
p=0.001
0.89±0.11
0.39±0.10
0.5
0
Conventional Ramipril
0
STRATUM - 1
STRATUM - 2
U. Prot. 1-3 g/24 h
U. Prot. ≥ 3 g/24 h
Kidney survival: Conventional 54 %
14
Ramipril 77 %
GISEN Group, Lancet, 1997
1.6
% patients with doubling of baseline creatinine or ESRF
(ml/min/month)
Mean rate of GFR decline
REIN CORE
Conventional
Ramipril
1.4
1.2
1.0
0.8
0.6
60
50
40
30
0.4
20
0.2
10
0
0
3 - 4.5 4.5 - 7
≥7
Baseline proteinuria (g/24 h)
15
70
3 - 4.5 4.5 - 7
≥7
Baseline proteinuria (g/24 h)
GISEN Group, Lancet, 1997
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
60
p < 0.05
60.0
50
40.4
40
20
10
21.4
Ramipril
30
Conventional
Incidence of ESRD (%)
70
p < 0.01
13.4
0.0
0
GFR (ml/min)
10.9
Lowest
Middle
Highest
(10.5 - 32.6)
(32.6 - 50.8)
(50.8 - 101.0)
TERTILES
16
Ruggenenti et al., J Am Soc Nephrol, 2002
EFFICACY AND SAFETY OF BENAZEPRIL IN PATIENTS WITH
ADVANCED CHRONIC RENAL INSUFFICIENCY (ESBARI)
A randomized controlled trial
Patients:
224 subjects with non-diabetic chronic nephropathies
Inclusion criteria:
S. creatinine: 3.1- 5.0 mg/dl
Treatment:
Benazepril
Placebo
Follow-up:
3.4 years (mean)
Outcomes
Primary:
Secondary:
Doubling of s. cretinine, ESRD or death
Proteinuria
(20 mg/day)
Hou et al., 2005
17
EFFICACY AND SAFETY OF BENAZEPRIL IN PATIENTS WITH
ADVANCED CHRONIC RENAL INSUFFICIENCY (ESBARI)
creatinine,ESRD, or death (%)
Patients without doubling serum
A randomized controlled trial
100
80
Benazepril
60
Placebo
40
20
0
0
12
24
36
Months of follow-up
18
Hou et al., 2005
LESS PROGRESSION TO ANURIA IN 60 PERITONEAL DIALYSIS
PATIENTS DURING 1-YEAR ACE INHIBITOR THERAPY
A prospective randomized study
100
80
60
40
20
0
Placebo
Ramipril
(5 mg/day)
Target blood pressure: <135/85 mmHg
19
Philips et al., J Am Soc Nephrol, 2002
ACE INHIBITORS AND SURVIVAL OF HEMODIALYSIS PATIENTS
A retrospective analysis (1994-2000) at a single Institution
Cumulative survival (%)
100
80
ACEi YES
n = 60
60
p < 0.0006
40
20
ACEi NO
n = 68
0
0
20
40
60
80
100
months
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
20
Efrati et al., Am J Kidney Dis, 2002
45
Ramipril
Ramipril
D GFR = -0.44 ± 0.54
(ml/min/month)
GFR
40
D GFR = -0.10 ± 0.50
35
30
25
D GFR = -0.81 ± 1.12
Conventional
CORE
21
D GFR = -0.14 ± 0.87
Ramipril
FOLLOW-UP
Ruggenenti et al., Lancet, 1998
0,10 ml/min/month
22
Cohorts ≥ 36 months
≥ 42 months
≥ 48 months
≥ 54 months
CONTINUED RAMIPRIL
D GFR (ml/min/month)
45
40
35
30
25
-.33 -.30
-.24 -.23
-.20
-.21 -.18
-.16
-.24 -.19 -.17
20
0
18 30
0
18
30 42
0
18 30 42
0
18 30 42
months
SWITCHED RAMIPRIL
DGFR (ml/min/month))
45
40
35
30
25
-.46 -.52
20
0
23
18 30
-.46 -.52 -.49
0
18
30 42
-.28 -.46 -.45
0
18 30 42
-.45 -.51 -.53
0
18
30 42
months
Ruggenenti et al., J Am Soc Nephrol, 1999
CONTINUED RAMIPRIL
SWITCHED RAMIPRIL
≥ 60 months
Cohorts
≥ 60 months
45
D GFR (ml/min/month)
40
35
30
25
-.16 -.13 -.11
-.10
-.25 -.35 -.44 -.30
20
0
24
18 30 42 60 months
0
18 30 42 60 months
Ruggenenti et al., J Am Soc Nephrol, 1999
REMISSION
REGRESSION
16 patients with stable D GFR
10 patients with increasing D GFR
GFR (ml/min/month)
Change in proteinuria
(post- vs pre- breakpoint)
- 31 %
- 52 %
90
90
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
0
10
20
30
months
40
50
60
0
10
20
30
40
50
60
months
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)
25
Ruggenenti et al., J Am Soc Nephrol, 1999
EVIDENCE FOR GLOMERULAR CAPILLARY REGENERATION AND
REABSORPTION OF SCLEROSIS AREAS
100
MWF 60 w
80
Number of glomeruli (%)
60
100
40
MWF 50 w
80
20
60
0
0
40
25-50 50-75
>75 %
100
MWF 60 w + LIS
20
0
<25
80
0
<25
25-50 50-75 >75 %
% sclerotic changes
60
40
20
0
0
26
Remuzzi et al., J Am Soc Nephrol, 2003
<25
25-50
50-75
>75 %
MWF 60 W
MWF 50 W
#1
#60
#1
#60
#20
#80
#40
#100
MWF 60 W + LISINOPRIL
#20
#40
27
#80
#1
#60
#20
#80
#40
#100
#100
Definitions of progression, remission, and regression of proteinuric
chronic nephropathies
Variable
Proteinuria
Glomerular filtration rate
Renal structural changes
Progression
Remission
Regression
≥ 1 g/24 h
Declining*
Worsening
< 1 g/24 h
Stable
Stable
< 0.3 g/24 h
Increasing
Improving
*Faster than physiological decline associated with aging (1 ml/min/1.73 sqm per year)
Ruggenenti et al., THE LANCET • Vol 357 • May 19, 2001
28
NON-DIABETIC CHRONIC NEPHROPATHIES
Ramipril
(n = 20)
GFR
3
70
2
60
ml/min
g/24 hours
Proteinuria
1
50
0
40
0
6
12
months
29
18
24
0
6
12
months
18
24
CAN WE DO BETTER?
protein traffic
Up-titrate ACE inhibitor dose
Intensify blood pressure control
Combine with other antiproteinuric agents
- Non-dihydropyridinic Ca-channel blockers
- Ang II receptor blockers
- Aldosterone antagonists
Vasopeptidase inhibitors
Low-protein diet
consequences of protein traffic
Drugs targeted to inflammatory or vasoactive genes which are
up-regulated by protein reabsorption
30
- ET-1 receptor antagonists
- TGFb inhibitors
- Lipid lowering agents
- C3 inhibitory agents
24 h Proteinuria*
M.A.P.*
y=-1.23x - 12.07
r =-1.23; p<0.02
D vs. no treatment (%)
0
-10
+10
-20
0
-30
-10
-40
-20
-50
-30
-60
-30
0
5
10
15
20
Ramipril dose (mg/day)
* No correlation between proteinuria and BP changes
31
+20
0
5
10
15
Ramipril dose (mg/day)
20
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 EneIordache, 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*
32
Lancet 2005; 365: 939-46
REIN-2
Patients:
335 subjects with non-diabetic chronic nephropathies
Inclusion criteria: Proteinuria > 1 g/24 hours
Cr. Cl.
< 70 ml/min/1.73 sqm
Treatment:
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
Follow-up:
19 (I.Q.R.: 12-35) months
Outcomes:
ESRD
DGFR (in a sub-group)
33
MEAN ARTERIAL PRESSURE IN EACH STUDY ARM
Mean arterial pressure
(mmHg)
104
102
100
Ramipril
98
Ramipril +
Felodipine
96
94
92
90
0
3
6
9
12
15
18
21
24
Months
34
Ruggenenti et al., Lancet, 2005
REIN-2
Ramipril +
Felodipine
45
Subjects with ESRD (%)
40
Ramipril
35
30
25
20
15
10
5
0
0
6
12
18
168
167
158
155
121
126
84
88
No. at risk
Usual BP
Lower BP
35
24
30
36
Follow-up (months)
64
59
50
51
34
43
42
24
31
48
13
17
54
2
0
Ruggenenti et al., Lancet, 2005
Lancet, 2005
Renoprotective therapy: is it blood
pressure or albuminuria that matters?
Paul E. De Jong, Dick de Zeeuw
36
A CASE-CONTROL STUDY OF SINGLE OR DUAL RAS INHIBITION IN
PATIENTS WITH NON-DIABETIC CHRONIC NEPHROPATHIES
Ramipril
(n = 20)
Benazepril + Valsartan (n = 20)
GFR
3
70
2
60
* p < 0.01
1
50
*
0
0
6
*
12
months
37
ml/min
g/24 hours
Proteinuria
*
*
40
18
24
0
6
12
months
18
24
Patients without events * (%)
COOPERATE study: results
100
Combination
Losartan
Trandolapril
80
60
40
20
0
0
6
12
18
24
30
36
Months after randomisation
* ESRD and doubling of serum creatinine
38
Nakao et al., Lancet, 2003
800
Treatment for 10 months (start treatment at 2 months)
600
(mg/day)
Urinary protein excretion
SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)
*
400
200
*
60
(%)
Glomerulosclerosis
0
80
40
*
*
20
*
Vehicle
39
Lisinopril
Lis + AII-RA
Lis + AII-RA
+Cerivastatin
Control
Zoja et al., J Am Soc Nephrol, 2002
REMISSION CLINIC
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
K < 5.5 mEq/l
K > 5.5 mEq/l
Add AII RA or ACE i
Up-titrate AII RA or ACE i to
maximum dose
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
40
Add a lipid lowering agent
Ruggenenti et al., Lancet, 2001
REMISSION CLINIC
Targets of the multidrug approach:
Blood pressure
Proteinuria
LDL
LDL + VLDL
HbA1c
< 120/80 mmHg
< 0.3 g/24 h
< 100 mg/dl
< 130 mg/dl
< 7.5 % (diabetics)
Ruggenenti et al., Lancet, 2001
41
- Full remission of nephrotic syndrome (U.prot. <1g/24 h) in 25 patients
- Stable s. creatinine
Remission clinic
4
(g/24 hours)
3
4
2
2
1
0
- 12
-6
0
6
12
months
18
24
24 - 50
Serum creatinine
6
0
42
5
(mg/dl)
Urinary protein excretion
8
- Residual proteinuria > 1g/24 h in 11 patients
Remission clinic
5
(g/24 hours)
6
4
3
4
2
2
0
1
0
- 12
-6
0
43 * 2 patients progressed to ESRD
6
12
months
18
24
> 24
Serum creatinine
*
(mg/dl)
Urinary protein excretion
8
TYPE 2 DIABETES
FULL-RESPONDERS (n=5)
- Full remission of nephrotic syndrome (U.prot. <1g/24 h)
- Stable s. creatinine
3
(g/24 hours)
2
4
1
2
0
-6
0
6
12
months
18
24
> 24
Serum creatinine
6
0
44
Remission clinic
(mg/dl)
Urinary protein excretion
8
TYPE 2 DIABETES
PARTIAL-RESPONDERS (n=13)
- Residual proteinuria > 1g/24 h
Remission clinic
3
(g/24 hours)
2
4
1
2
0
45
0
-6
0
6
12
months
18
24
> 24
Serum creatinine
6
(mg/dl)
Urinary protein excretion
8
TYPE 2 DIABETES
200
Remission clinic
SBP
180
160
Responder
(mmHg)
Non-Responder
140
120
100
80
Responder
Non-Responder
60
40
46
-6
0
6
12
18
24
> 24
Non-diabetic proteinuric
nephropathies
25
Diabetic nephropathy
25
25
20
15
11
10
Number
Number
20
15
10
5
5
0
0
NonResponders responders
13
5
NonResponders responders
p < 0.01 non-diabetic proteinuric nephropathy vs diabetic nephropathy (Chi square test)
47
SWIMMING TO REDUCE PROTEINURIA?
20 patients: proteinuric chronic nephropathy
Treatments: 12-week regular acquatic exercise
Proteinuria
Blood pressure
p < 0.01
p = 0.005
1.5
150
140
1.0+0.3
120
g / 24h
mmHg
130
p < 0.05
1.0
0.5+.03
100
90
80
0.5
70
Pre
48
Post
Pre
Post
Pechter et al., Nephrol Dial Transplant, 2003
A swimming pool for the
Clinical Research Center?
49