Transcript Document

Giuseppe Remuzzi
Prevention of progression and
remission/regression strategies of
chronic renal diseases:
can we do better now than 5
years ago?
Bellagio, March 16, 2004
1
There are 1,065,000 people on
dialysis worldwide
90 % of them live in North
America, Japan, and Europe,
whose population is less than 20 %
of world population
2
PREDICTED DIALYSIS COST OF APPROXIMATELY
$ 1.1 TRILLION FOR THE COMING DECADE
Ten year medical costs of
dialysis population
$ ( billions)
1200
1000
800
600
400
200
0
1981-1990
1991-2000
2001-2010
Lysaght et al., J Am Soc Nephrol, 2002
3
1,000,000 deaths
4
PROGRESSION OF RENAL FAILURE IN 9 DIABETICS
80
1/Cr x 10 3 (µmol/l)
60
40
20
0
0
10
20
30
40
50
Time (months)
Jones et al., Lancet, 1979
5
700
DEATH
IN
*
600
(mg/24 hrs)
500
400
300
200
100
**
Percentage of glomeruli
affected by sclerosis
0
Control
100
UNx
UNx + Lis
*
Control
UNx + Lis
100
80
Survival (%)
Urinary Protein Excretion
ACE INHIBITION PREVENTS RENAL FAILURE AND
UNINEPHRECTOMIZED MWF/ZTM RATS
60
40
20
**
80
60
40
20
UNx
0
0
Control
* p < 0.05, **p < 0.01 vs control
UNx
UNx +
Lis
0
3
6
9
12
15
Time (months after UNx)
Remuzzi et al., Kidney Int, 1995
6
EFFECT OF ACE-I THERAPY ON RISK OF DEATH IN NON-DIABETIC
CHRONIC RENAL DISEASE
Risk of death
Patients
- Zucchelli et al., 1992
121
- Kamper et al., 1992
70
- Brenner et al., 1993
112
- Toto et al., 1993
124
- van Essen et al.,1994
103
- Hannedouche et al., 1994
100
- Bannister et al., 1994
51
- Hansson et al., 1995
260
- Ihle et al., 1996
- Maschio et al., 1996
Risk Ratio & C.I.
60
70
583
Pooled Risk Ratio (95% CI)
- OVERALL
1594
1.24 (0.55 - 2.83)
ACE-I better
0.01
0.05
0.2
ACE-I worse
1
5
20
Patients with proteinuria (%)
Author, year
50 %
35 %
30
15 %
0
< 0.5
100
0.5 - 3
≥3
Proteinuria (g/24 h)
Giatras et al, J Am Soc Nephrol, 1997
7
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)
p=0.001
Rate of GFR decline
(ml/min/month)
Rate of GFR decline
1.0
0.89±0.11
0.39±0.10
0.5
0
Conventional Ramipril
0
STRATUM - 1
STRATUM - 2
U. Prot. < 3 g/24 h
U. Prot. ≥ 3 g/24 h
Kidney survival: Conventional 54 %
Ramipril 77 %
GISEN Group, Lancet, 1997
8
Conventional
Ramipril
% patients with doubling of baseline creatinine or ESRF
1.6
(ml/min/month)
Mean rate of GFR decline
REIN CORE
1.4
1.2
1.0
0.8
0.6
0.4
70
60
50
40
30
20
0.2
10
0
0
3 - 4.5 4.5 - 7
≥7
Baseline proteinuria (g/24 h)
3 - 4.5 4.5 - 7
≥7
Baseline proteinuria (g/24 h)
GISEN Group, Lancet, 1997
9
AN ARTIFICIAL NEURAL NETWORK TO MODEL INDIVIDUAL
OUTCOME OF PATIENTS WITH CHRONIC NEPHROPATHIES
ON THE BASIS OF DATA FROM THE REIN STUDY
Besides serum creatinine, the model identified proteinuria and
Ca*P product as the strongest predictors of ESRD
10
RISK OF PROGRESSION TO ESRD OVER 20 MONTHS
FOLLOW-UP IN PROTEINURIC CHRONIC NEPHROPATHIES
80
Predicted risk in 3 explicative cases
%
60
40
20
1.2
1.9
24.3
2.1
3.9
35.1
3.5
5.2
37.2
Serum creat mg /dl
Proteinuria g /24 h
CaxP
mg2/dl2
0
11
3 MONTHS PROTEINURIA REDUCTION PREDICTS LONG-TERM GFR
DECLINE
The REIN study
- 0.9
Ramipril
Overall
Conventional
> 3 gr/24 h
- 0.7
3 years
GFR (ml/min/month)
- 0.8
- 0.6
-0.5
- 0.4
-0.3
-0.2
- 20
0
20
40
 proteinuria *
( percent change vs .baseline)
3 months
* Corrected for GFR
Perna et al., J Am Soc Nephrol, 2000
12
1 - 3 gr/24 h
40
Placebo
- 0.7
- 0.8
0.9
- 20
-0.3
- 0.4
> 3 gr/24 h
40
3 months
( percent change vs .baseline)
Overall
0
- 0.2
 proteinuria *
Ramipril
20
3 months
(percent change vs. baseline)
 proteinuria *
CORRELATION BETWEEN CHANGES IN PROTEINURIA AND GFR DECLINE
20
0
- 20
-0.2
-0.3
* Corrected for GFR
- 0.4
-0.5
- 0.6
GFR (ml/min/month)
3 years
Perna et al., J Am Soc Nephrol, 2000
13
6 MONTHS PROTEIN/CREATININE RATIO REDUCTION
PREDICTS RENAL AND CARDIOVASCULAR EVENTS
The RENAAL study
Hazard ratio (95 % C.I.)
ESRD
CV events
Heart failure
Increased risk
Decreased risk
0.2
0.4
0.6
0.8
1
1.2
RENAAL Study group, 2002
14
PROTEINURIA AND RISK OF DEVELOPING ESRD
Community-based screening in 106,177 general population
Cumulative incidence of ESRD (%)
Follow-up: 17 years
16
14
12
10
8
6
4
2
0
Proteinuria
Number of screened
Number of ESRD
-
+
+
2+
>3+
86,253
10,000
4,007
1,072
357
185
38
55
76
55
Iseki et al., Kidney Int, 2003
15
RISK OF ESRD: PREDICTIVE VALUE OF BASELINE
GFR AND PROTEINURIA
1993 mass screening conducted by the Okinawa General
Health Maintenance Association (OGHMA)
Subjects
95,255
Inclusion criteria
> 20 years of age
GFR > 15 ml/min
Baseline parameters
Dipstick proteinuria
Calculated GFR (Cockcroft-Gault method)
Follow-up
7 years
End point
ESRD
Iseki et al., J Am Soc Nephrol, 2003
16
Cumulative Incidence of ESRD
per 1,000 screened in 7 years
Fig3
80
Proteinuria (+)
Proteinuria (-)
60
40
20
0
15.0-57.1
57.2-77.6
77.7-102.6
≥102.7
Total
GFR, ml/min/1.73m2
Proteinuria (+)
Number of screened
Number of ESRD
1,125
84
811
11
717
7
800
6
3,453
108
21,872
22
22,254
18
22,312
1
22,229
3
88,667
44
Proteinuria (-)
Number of screened
Number of ESRD
17
EFFECTS OF LOSARTAN ACCORDING TO RACE:
Post-hoc analyses of the RENAAL study
Region
n°
Primary end point
p
(Doubling s. creat, ESRD or death)
Hazard ratio (95 % C.I.)
Asian
252
0.024
Black
230
0.94
White
734
0.07
Hispanic
277
0.99
19
0.76
1,261
0.18
Other
Overall
Losartan worse
Losartan better
0.25
0.5
0.75
1.0
1.25
1.5
The whole effect of Losartan was fully driver by Asian patients
18
1-YEAR PROTEINURIA REDUCTION IN TYPE 2 DIABETICS ENROLLED
IN THE RENAAL STUDY ACCORDING TO RACE
ASIA
Non-ASIA
n = 252
n = 1,261
Median (I.Q. range) proteinuria
reduction vs baseline (%)
0
-5
-10
-9
(-51 to 40)
-15
-20
-19
(-56 to 36)
p = 0.03
(ANCOVA)
19
Baseline
proteinuria
p
Reduced Outcome
proteinuria improved
(alb/creat g/g)
Risk reduction (95 % C.I.)
Asian
1.535
Non Asian 1.167
YES
YES
0.016
NO
NO
0.27
YES
NO
NO
NO
0.59
0.35
Increased risk
Decreased risk
-75
-50
-25
1
25
50
75
20
BASELINE CHARACTERISTICS OF ASIAN AND
NON-ASIAN PATIENTS OF RENAAL STUDY
p
Asian
Non-Asian
(257)
(1256)
60+7
60+7
0.72
MAP (mmHg)
102+11
106+11
<0.005
BMI (Kg/m2)
25+4
31+5
<0.0001
Age (yrs)
21
45
Ramipril
Ramipril
 GFR = -0.44 ± 0.54
(ml/min/month)
GFR
40
 GFR = -0.10 ± 0.50
35
30
 GFR = -0.81 ± 1.12
 GFR = -0.14 ± 0.87
25
Conventional
CORE
Ramipril
FOLLOW-UP
Ruggenenti et al., Lancet, 199822
0,10 ml/min/month
23
Regression
16 patients with stable  GFR
10 patients with increasing  GFR
90
90
80
80
70
70
GFR (ml/min/month)
GFR (ml/min/month)
Remission
60
50
40
30
60
50
40
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)
24
RELATIONSHIP BETWEEN REMISSION/REGRESSION
BREAKPOINT CHANGES IN PROTEINURIA
Post hoc analyses of the REIN study
Remission
Regression
n = 16
n = 10
AND
POST-
- 20
(%)
Proteinuria reduction vs
pre-breakpoint values
0
-31 %
- 40
-52 %
- 60
The further improvement in GFR during continued ramipril therapy was always
associated with further proteinuria reduction
The extent of GFR amelioration was associated with the extent of proteinuria
reduction
Ruggenenti et al., J Am Soc Nephrol, 1999
25
REGRESSION OF THE DISEASE IN PATIENTS ON
CONTINUED RAMIPRIL
50
GFR (ml/1.73 sqm)
40
30
*
20
Y1 = - 0.3291x + 44.794
10
Y2 =0.387x + 19.677
p (y1 vs y2 ): < 0.01 (F-test)
*
Y= 0.0092x - 0.6033x2 + 45.586
0
0
6
12
18
24
30
36
42
48
54
months
26
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
40
<25%
25-50% 50-75%
>75%
100
MWF 60 w + LIS
20
0
0%
80
0%
<25% 25-50% 50-75%
>75%
60
40
20
0
Remuzzi et al., J Am Soc Nephrol, 2003
0%
<25%
25-50% 50-75%
>75%
27
CAN WE DO BETTER?
protein traffic
Intensify blood pressure control
Up-titrate ACE inhibitor dose
Combine with other antiproteinuric agents
- Non-dihydropyridinic Ca-channel blockers
- Ang II receptor blockers
- Aldosterone antagonists
Vasopeptidase inhibitors
consequences of protein traffic
Drugs targeted to inflammatory or vasoactive genes
which are up-regulated by protein reabsorption
- ET-1 receptor antagonists
- TGFb inhibitors
- Lipid lowering agents
28
THE EFFECT ON PROTEINURIA AND BLOOD PRESSURE OF
INCREASING DOSES OF ACE INHIBITORS
24 h Proteinuria*
M.A.P.*
y=-1. 23x - 12. 07
r =-1.23; p<0. 02
 vs. no treatment (%)
0
+20
-10
+10
-20
0
-30
-10
-40
-20
-50
-30
-60
-30
0
5
10
15
20
Ramipril dose
(mg/day)
0
5
10
15
20
Ramipril dose
(mg/day)
* No correlation betw een proteinuria and BP changes
29
THE COURSE OF THE EFFECT OF ANG II ANTAGONISM ON
BLOOD PRESSURE AND URINARY PROTEIN EXCRETION
Blood pressure
Urinary protein
excretion
Gansevoort et al., Kidney Int, 1994
30
Changes vs. basal (%)
EFFECTS OF UP-TITRATING
MEMBRANOUS NEPHROPATHY
LISINOPRIL
IN
+ 40
+ 30
+ 20
Serum Albumin
+ 10
0
- 10
- 20
- 30
LDL Cholesterol
0
10
20
30
40
10
0
Lisinopril dose (mg/day)
Ruggenenti et al., Circulation, 2003
31
DUAL RENIN-ANGIOTENSIN SYSTEM BLOCKADE IS HIGHLY EFFECTIVE
TO IN NON-DIABETIC PROTEINURICS
9 non-diabetic renal patients (6 weeks treatment per dose)
Change of proteinuria (%)
0
-25
Losartan
-50
-75
Lisinopril
Combined
-100
0
50
100
150
50 - 150
0
10
20
40
10 - 40
Laverman et al., Kidney Int, 200232
EFFECTS ON PROTEINURIA OF 8 WEEKS COMPARABLE BLOOD PRESSURE
CONTROL ACHIEVED BY COMBINED THERAPY IN 23 PATIENTS WITH
CHRONIC NON-DIABETIC NEPHROPATHIES
10
BENAZEPRIL
(20 mg/day)
VALSARTAN
(160 mg/day)
Percent change from baseline
0
BENAZEPRIL +
VALSARTAN
(10 + 80 mg/day)
-10
-20
-30
-40
24 hrs Uprot excretion
MAP
-50
-60
p = 0.022
p = 0.024
-70
p = 0.002
Campbell et al., 2002
33
Dextran Fractional Clearance
1.0
*
*
0.1
*
*
*
*
*
**
*
**
**
**
**
**
**
*
0.01
Baseline
*
22
30
38
46
54
62
70
38
**
Basaline
**
**
Valsartan
22 30
**
**
Baseline
*
Benazepril
**
**
**
46
54
62
**
Benazepril + Valsartan
*
70
**
**
*
22
30
38
46
54
62
70
Molecular radius (Å)
Dextran clearance studies found no differences in size selective properties of the
membrane but more reduction in renal vascular resistance (p = 0.046) in
combination therapy compared to each drug alone
Campbell et al., 2002
34
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
Nakao et al., Lancet, 2003
35
800
Treatment for 10 months (start treatment at 2 months)
(mg/day)
Urinary protein excretion
SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)
600
*
400
200
*
60
(%)
Glomerulosclerosis
0
80
40
*
*
20
*
Vehicle
Lisinopril
Lis + AII-RA
Lis + AII-RA
+Cerivastatin
Control
Zoja et al., J Am Soc Nephrol, 2002
36
EDITORIAL
J Am Soc Nephrol 13:3024 - 3026, 2002
The Next Treatments of Chronic Kidney Disease: If
We Find Them, can We Test Them?
THOMAS H. HOSTETTER
National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, Maryland
37
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
Add a lipid lowering agent
Ruggenenti et al., Lancet, 2001
38
FULL RESPONDERS (n=19)
- Full remission of nephrotic syndrome (U.prot. <1g/24 h)
- Stable s. creatinine over 4 years
5
Remission clinic
4
(g/24 hours)
3
4
2
2
1
0
0
- 10
Serum creatinine
6
(mg/dl)
Urinary protein excretion
8
0
10
20
months
30
40
50
39
PARTIAL RESPONDERS (n=7)
- Partial remission of nephrotic syndrome
- s. creat increase < 0.2 mg/dl/year
Remission clinic
5
(g/24 hours)
6
3
4
2
2
Serum creatinine
4
(mg/dl)
Urinary protein excretion
8
1
0
-10
0
0
20
10
30
40
months
40
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
OUTCOMES OF 160 TYPE 2 DIABETICS WITH
MICROALBUMINURIA ACCORDING TO MULTIFACTORIAL
OR CONVENTIONAL THERAPY
Relative risk (95 % C.I.)
Fatal and non-fatal CV events
Nephropathy
Retinopathy
Multifactorial
therapy better
0.0
0.5
Multifactorial
therapy worse
1.0
1.5
2.0
Gaede et al., N Engl J Med, 2003
42
When to start, why never stop
43
INCIDENCE OF ESRD IN 352 PATIENTS WITH
PROTEINURIC, CHRONIC NEPHROPATHIES ACCORDING
TO TREATMENT AND TERTILES OF BASAL GFR
Incidence of ESRD (%)
70
60
p < 0.05
60.0 %
50
40.4 %
20
10
21.4 %
Ramipril
30
Conventional
40
p < 0.01
13.4 %
10.9 %
0.0 %
0
Lowest
Middle
Highest
(10.5 - 32.6 ml/min)
(32.6 - 50.8 ml/min)
(50.8 - 101.0 ml/min)
Ruggenenti et al., J Am Soc Nephrol, 2002
44
1998 - 2010
PREDICTED ESRD PREVALENCE AND CUMULATIVE SAVINGS FOR
DIFFERENT DEGREES OF GFR REDUCTIONS
ESRD
7.56
65,000
0
661,330
615,767
60,000
55,000
-10 %
50,000
466,438
45,000
-30 %
40,000
- 10 %
- 30 %
10
20
18,56
30
40
50
60
60,61
35,000
2000
GFR reduction*
Prevalence
projections
Costs saved ($ billion)
Prevalence
Predicted
GFR
(ml/min/yrs)
70
2005
2010
* Predicted for patients with basal GFR ≤ 60ml/min
Hariprasad et al., Am J Kidney Dis, 2002
45
 GFR (ml/min/month)
GFR DECLINE ACCORDING TO DIFFERENT UNDERLYING RENAL DISEASE
1.2
Conventional
Ramipril
1.0
0.8
0.55±0.13
0.6
0.53±0.09
0.49±0.11
0.36±0.09
0.4
0.31±0.09
0.31±0.07
0.2
0
Primary Glomerular
IgA
Nephropathy
Nephrosclerosis
-35
-37
Disease
% GFR
-42
reduction vs control
Ruggenenti et al., Am J Kidney Dis, 2000
46
DEVELOPMENT OF A LOW COST “POLYPILL” TO
PREVENT
RENAL
PROGRESSION
AND
CARDIOVASCULAR EVENTS
• A single combination low cost pill containing six active
components,
including
aspirin,
a
statin,
three
antihypertensive agents (a thiazide, a b-blocker, an ACE
inhibitor) at half standard dose, and folic acid has been
proposed for the prevention of cardiovascular disease
Wald and Law, British Med J, 2003
47
Statin
Aspirin
ACE
inhinitors
The superpill could be valuable also for patients with
chronic nephropathies to limit both renal and
cardiovascular events
48
A LOW COST POLYPILL COULD USE
GENERIC COMPONENTS
Generic drugs are not subject to patent
protection
This formulation may not have the lowest
rate of adverse effects, but even if about
10% of people were intolerant of the
formulation it would still have considerable
public health merit
49
So far, treatment of renal patients has
been aimed to limit or prevent
progression to ESRD
50
ANNUAL ESRD AND MORTALITY IN TYPE 2 DIABETICS
WITH OVERT NEPHROPATHY
25
(%)
°
20
15
?
10
*
5
0
Mortality
ESRD
Estimate from the °UKPDS and the *RENAAL studies
Adler et al., Kidney Int, 200351
Preventing nephropathy
is more important than
retarding progression
52
PROJECTED CHANGES OF ISCHEMIC HEART
DISEASE MORTALITY WORLDWIDE
(1990 to 2020)
5000
Deaths (x 1000) 4500
DEVELOPING
COUNTRIES
4000
3500
3000
2500
2000
1500
1000
500
0
DEVELOPED
COUNTRIES
1990
2020
Yusuf et al. Circulation 2001
The obstacle in providing adequate health care
to millions of people in poor countries are
multiple
- Poor infrastructures
- Famine and malnutrition
- Cultural attitudes
- Inadequate public health systems
- War
54
However, lack of access to
essential drugs is a most
striking aspect that underlines
dramatically the existence of
two different world
55
THE KIDNEY HELP TRUST PROJECT IN INDIA
25,000 people were screened for high
blood pressure, diabetes, chronic kidney
disease in the region of Tamil Nadu (India)
The screening campaign was conducted by
6 trained social workers and 2 doctors
India
Tamil Nadu
Patients with high blood pressure, diabetes
or kidney diseases were put on cheap
medications and followed
- COST OF 1 YR OF THE PROJECT
- COST PER PATIENT
- PER CAPITA HEALTH EXPENDITURE
$
$
$
6,200
0.27
7.7
IN INDIA
Mani, Kidney Int, 2003
56
The community programme of
mass screening and free drug
therapy, reported from India would
not be sustainable if replicated
across the whole of India
57
STARTING
TO
WORK
FOR
A
LARGE-SCALE
PREVENTION PROGRAM OF ESRD IN MOLDOVA
MOLDOVA
Chisinau
Bergamo
4,762,000 population
33,700 Km2
Income per month: 70 $
Network between existing health
care structures under the
coordination of the Republican
Clinical Hospital Chisinau
Large--scale screening
Intervention treatment
Continuous education
Health Authorities
Mario Negri Institute
Activation
of a 4 yr
program
Moldova Society of
Nephrology
Igor Codreanu
ISN-COMGAN
58
VIRTUAL NETWORKS OF EXCELLENCE TO
LINK THE SCIENTIFIC TALENTS OF ENTIRE
REGIONS
Virtual networks of excellence are based on
research programs jointly sponsored and
conducted by research institutes in different
geographical locations
InterAcademic Council, 2004
59
CREATING AUTONOMOUS CENTERS OF
EXCELLENCE TO ADDRESS LOCAL
CHALLENGES
Center of excellence - whether of local,
national, regional, or international status should be created or planned in the near
future in every developing nation in order for
its science capacity to grown
InterAcademic Council, 2004
60
THE EFFECT OF RAMIPRIL TRIALS ON ACE INHIBITOR
PRESCRIBING IN ONTARIO (CANADA)
REIN, HOPE
All ACE inhibitors
Ramipril
61
62
PERCENT PROFIT OF TOP COMPANIES IN EACH SECTOR
20
18,6
%
15
11,7
10
5,7
5
5,1
3,5
0
Pharmaceutical Telecom
Airlines
Chemicals Automobiles
Fortune 500, 2000
63
PHARMACEUTICAL COMPANIES
Year 2000
Percent of income
30
20
10
0
Marketing
Research
Fortune 500, 2000
64
INVESTMENT OF PUBLIC INSTITUTIONS ON
INNOVATIVE DRUGS
Pre-clinical studies
Infrastructures
Expertise
- physicians
- nurses
- other professionals
Angell, N Engl J Med, 2000
65
It is no unlikely that the preclinical research could account
for as much as 20 to 25% of a
company’s research budget
Gerth and Stolberg, New York Times, 2000
66
It
is
becoming
increasingly
intolerable to know that innumerable
lives are lost in poor countries only
because relatively simple measures
are not available because of their cost
The contribution of pharmaceutical
industry is fundamental to starting a
new era of hope
67
A GLOBAL FUND FOR KIDNEY DISEASE
68
Pharmaceutical companies that profit
from selling renoprotective drugs
take the lead in establishing the fund
The
makers
of
drugs
with
renoprotective effects - not just ACE
inhibitors and ARBs, but also blood
pressure, diabetes, and cholesterol
drugs - could donate 1 % of profit
from sales of these drugs
69
WHAT TO DO WITH GLOBAL FUND?
Further ISN prevention/education program
and add primary care physicians and health
professionals
Begins
centers
of
excellence
with
infrastructures so we can apply to agencies
for funds
Raise public awareness to renal survival
70
CORPORATE SOCIAL RESPONSIBILITY
The one % solution:
1 % of equity
1 % of profit
1 % of employees’ paid hours are devoted to
philanthropy
Compassionate
capitalism
benefits
the
shareholders, the employees and the needy
people
Marc Benioff, Salesforce
71
72
Helping patients of a less
developed country is a way
to thank the contribution of
so many volunteers
73
The industry's impact on public
health is so great, and the subsidies
and
protections
offered
by
governments so generous, that the
industry should consider its social
responsibilities
74
75
These slides are belonging to
Giuseppe Remuzzi, M.D.
Mario Negri Institute for Pharmacological
Research, Bergamo, Italy.
Using these slides is only authorized by
mentioning the source
76
BASELINE PROTEINURIA PREDICTS THE RESPONSE TO RAS
BLOCKADE
Post-hoc analyses of the RENAAL study
Alb/creat ratio
n°
Primary end-point
(doubling, ESRD or death)
(g/g)
Hazard ratio (95 % C.I.)
> 1.25
757
< 1.25
756
Overall
1,513
0.5
0.75
1.0
1.25
1.5
77
LESS NEED OF DIALYSIS FOR NON-DIABETIC AND DIABETIC RENAL
DISEASE WITH RENIN-ANGIOTENSIN SYSTEM BLOCKADE
REIN
CAPTOPRIL
RENAAL
IDNT
(n = 352)
(n = 409)
(n = 1,513)
(n = 1,715)
0
Relative risk (%)
- 10
- 20
- 20 %
- 30
- 28 %
- 40
- 50
- 45 %
- 48 %
78
There is little doubt that ACE-I and
ARBs have guaranteed substantial
revenues, and their development
costs have been largely paid off,
since their sale is in the order of
billions of dollars worldwide
79
INCIDENCE OF ESRD IN 1513 PATIENTS WITH TYPE 2 DIABETIC
NEPHROPATHY ACCORDING TO TREATMENT AND TERTILES OF
BASAL SERUM CREATININE (data from the RENAAL study)
40
30
10
Losartan
20
Placebo
Incidence of ESRD (%)
50
0
S. Creatinine (mg/dl)
2.1 - 3.6
1.6 - 2.0
0.9 - 1.5
GFR (ml/min)
19 - 34
35 - 44
45 - 77
80
INCIDENCE OF HEART FAILURE IN 1513 PATIENTS WITH TYPE 2
DIABETIC NEPHROPATHY ACCORDING TO TREATMENT AND TERTILES
OF BASAL SERUM CREATININE (data from the RENAAL study)
p < 0.003
p < 0.01
25
21.3
19.3
15
13.4
11.3
11.0
5
9.0
Los
10
Placebo
Incidence (%)
20
0
S. creat
2.1 - 3.6
Lowest
1.6 - 2.0
Middle
0.9 - 1.6
Highest
TERTILES
81
mmHg
Control
0.08
0.07
Diabetic
0.06
0.05
0.04
0.03
0.02
**
400
*
300
200
100
0.01
Diabetes
Pore radii distribution
0.09
63
mmHg
Control
0.10
53
Urinary protein excre tion (mg/24 h)
P GC
0
0.00
0
10
20
30
40
Pore radius (Å)
50
60
0
4
8
12
months
Remuzzi et al., J Am Soc Nephrol, 1993
82
MAP (mmHg)
95
98
101
104
107
110
113
116
119
0
r = 0.69; p < 0.05
GFR (ml/min/year)
-2
-4
-6
-8
-10
-12
-14
130/85
140/90
Diabetes
Parving et al., Br Med J, 1989
Viberti et al., JAMA, 1993
Hebert et al., Kidney Int, 1994
Lebovitz et al., Kidney Int, 1994
Bakris et al., Kidney Int, 1996
Bakris et al., Hypertension, 1997
Untreated HTN
Non-diabetes
Klahr et al., N Engl J Med, 1993
Maschio et al., N Engl J Med, 1996
GISEN Group, Lancet, 1997
Bakris et al., Am J Kidney Dis, 2000
83
ACHIEVED BLOOD PRESSURE CONTROL IN
MAJOR TRIALS ON NEPHROPATHY TYPE 2
DIABETES
Trial
SPB/DBP (mmHg)
Study drug
RENAAL
142/74
Losartan
IDNT
142/84
Irbesartan
IRMA
144/77
Irbesartan
84
In the 2010
Diabetes
High blood pressure/chronic renal disease
Need of dialysis
30 millions
80 millions
1 million
CHINA
85
ANGIOTENSIN
II
PARTICIPATES
TO
THE
DEVELOPMENT OF GLOMERULAR CAPILLARY
HYPERTENSION
Acute infusion of Ang II in normal rats raises
intraglomerular capillary pressure
Myers et al., Circ Res, 1975
Following 5/6 nephrectomy in rats endogenous
Ang II local activity increases
Mackie et al, Kidney Int, 2001
86
RENAAL
Reduction of Endpoints in NIDDM with the AII Antagonist Losartan
ESRD
- 1513 type 2 diabetes
30
- Alb/Cr ratio >300 mg/g,
- S Creat 1.3-3.0 mg/dL,
% with event
- Age 31-70 years
P
20
Risk Reduction: 28%
L
p=0.002
10
0
0
12
24
36
48
Months
87
RENAAL: ARB IS BETTER THAN CONVENTIONAL
THERAPY IN TYPE 2 DIABETIC NEPHROPATHY
% with
Doubling of
Baseline
Creatinine
+ ESRD
+ death
0
Losartan
Conventional therapy
25
50
75
100
0
+2–
1
2
4
+ 40 –
0–
Decrease in
Mean Blood
Pressure
(mm Hg)
3
-2–
+ 20 –
-4–
% Reduction 0 –
in
Proteinuria - 20 –
-6–
-8–
-9–
- 10 –
-9.2
-9.6
NS
p <.001
+ 19
- 40 –
- 60 –
- 45
Brenner et al, N Engl J Med., 2001.
88
THE PROGRAMS OF PREVENTING
RENAL
DISEASE
PROGRESSION
WORLDWIDE
The funding of such programs is
probably on the top of list of the
difficulties
89
A GLOBAL FUND TO FIGHT RENAL
AND VASCULAR DISEASES
ISN: initiator and advisory body in creating the
Fund and executing the programs
Governed by WHO
90
The notion of health as a good
to be bought and sold be
cannot be a substitute for the
notion of health as a
fundamental human right
EFFECTS OF LOSARTAN ACCORDING TO THE GEOGRAPHIC AREA:
Post-hoc analyses of the RENAAL study
Region
n°
Primary end point
p
(Doubling s. creat, ESRD or death)
Hazard ratio (95 % C.I.)
North America
687
0.64
Europe
295
0.76
Latin America
274
0.54
Asia
257
0.0008
Overall (but Asia) 1,256
0.34
Losartan worse
Losartan better
0.25
0.5
0.75
1.0
1.25
1.5
The whole effect of Losartan was fully driver by Asian patients
92
1-YEAR PROTEINURIA REDUCTION IN ASIA AND NON-ASIA TYPE 2
DIABETICS ENROLLED IN THE RENAAL STUDY
ASIA
Non-ASIA
n = 257
n = 1,256
Median (I.Q. range) proteinuria
reduction vs baseline (%)
0
-5
-10
-9
(-51 to 43)
-15
-20
-20
(-55 to 30)
p < 0.05
(ANCOVA)
Less events in Asia patients were associated with more (double) short-term
proteinuria reduction
93
REIN:
ACE-I
IS
MORE
CONVENTIONAL THERAPY
DISEASE
RENOPROTECTIVE
THAN
IN NON-DIABETIC RENAL
100
% of
patients
without
doubling of
baseline
creatinine or
ESRF
Ramipril
80
Conventional therapy
60
P=0.02
40
20
0
0
100 –
Diastolic Blood
Pressure
(mm Hg)
90 –
80 –
70 –
60 –
6
12
18
24
Follow-up
30
36
- 40 –
- 20 –
% Reduction
in
Proteinuria
0–
20 –
40 –
60 –
Gisen group; Lancet 1997 94
treatment *
100
Glomerular Filtration Rate
(ml/min/1.73sqm)
80
60
GFR
20 ml/year
GFR
2 ml/year
40
20
DYALISIS
0
-2
-1
0
1
2
3
4
5 years
* PA 200/120 mmHg
Mogensen et al. , 1976
95
Diabetic nephropathy is irreversible in
human
No cases of recovery or cure have been
reported in the literature
Once the clinical signs of nephropathy
have become manifest, the natural
course is inexorably progressive to death
Kussman et al., JAMA, 1976
96
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
Post
Pre
Post
Pechter et al., Nephrol Dial Transplant, 200397
… a 22 years old women with previous diagnosis of Systemic Lupus Erythematosus
Losartan 50
Renal biopsy *
100 mg/day
Hydrochlorotiazide 25 mg/day
Low sodium diet 2 g/day
Enalapril 2.5
AZA 100
Prednisone 25
10
20 mg/day
5 mg/day
MPD
6
2
2
1
0
0
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Serum creatinine
3
4
(mg/dl)
Proteinuria (g/day)
8
2003
* Severe chronic glomerulopathy with no signs of disease activity
98
PREVENTING
MORTALITY?
NEPHROPATHY
WILL
PREVENT
CV
The BENEDICTstudy
ACE-I
1200 type 2 diabetics: BP>140/90 mmHg
Normoalbuminuria
Main end points:
ndCCB
Fatal and non-fatal CV events
Progression to microalbuminuria
Run-in
Targets:
Study End:
ACE-I + ndCCB
BP<120/80mhg
HbA1c <7,5%
Placebo
July 2003
0
1
2
3
Years
99
Science brings imagination and
vision to bear across the board
allowing people to analyze present
(and future) situations, make
sounder choices, and invest their
resources more wisely
InterAcademic Council, 2004
On August 30, 2003 World Trade
Organization reaches agreement
on generic medicines
101
IMPROVING ONLINE ACCESS TO MEDICAL INFORMATION
FOR LOW-INCOME COUNTRIES
WHO helped to create the Health InterNetwork Access to Research
Initiative (HINARI)
69
Low-income countries (GNP<$1,000) offered for free online
access to a large library of important international journals
44
Additional countries (GNP $1,000-3,000) qualified for
access to the journals at a very low price ($ 1,000 per year)
1043
Total institutions in 100 countries (of a total of 113 eligible
countries) have registered for the program
47
Publishers of scientific publishing have joined the Network
Access to offer more than 2,300 journals and other full-text
resources
Aronson, N Engl J Med, 2004
102
Pharmaceutical companies are not
the biggest industries in terms of
revenues, but are very profitable
The
pharmaceutical
companies
average profit is 18 % of revenues
as compared to 11.6 % of financial
companies
Henry and Lexchin, Lancet, 2002
103
The
pharmaceutical
industry
nowadays is a very profitable
enterprise, and its returns are on
the average greater than those of
other industries
104
RESPONSE TO ACE INHIBITION ACCORDING TO DIFFERENT
LEVELS OF BASELINE PROTEINURIA
1 .0
( ml/ min/ mo nt h)
Mean rat e of GFR decline
1 .2
Ramipril
Convent ional
0 .8
0 .6
0 .4
0 .2
0
n= 1 1 5
n= 6 0
n=81
n=69
<2
2 -3
3 -4 .5
•4 .5
Base-line urinary prot ein excret ion
(g/ 2 4 hours)
105