1 Giuseppe Remuzzi Prevention of progression and remission/regression strategies of chronic renal diseases: can we do better now than 5 years ago? Bellagio,

1

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

2

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

3Lysaght et al., J Am Soc Nephrol, 2002

1200

600

0

Te

n ye

ar

me

dic

al c

ost

s o

f d

ialy

sis

pop

ula

tion

$ (

bill

ions

)

1981-1990 1991-2000 2001-2010

800

1000

$

$

$

PREDICTED DIALYSIS COST OF APPROXIMATELY $ 1.1 TRILLION FOR THE COMING DECADE

400

200

4

1,000,000 deaths

5

PROGRESSION OF RENAL FAILURE IN 9 DIABETICS

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)

6

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 control Remuzzi et al., Kidney Int, 1995

7

EFFECT OF ACE-I THERAPY ON RISK OF DEATH IN NON-DIABETIC CHRONIC RENAL DISEASE

- Zucchelli et al., 1992

- Kamper et al., 1992

- Brenner et al., 1993

- Toto et al., 1993

- van Essen et al.,1994

- Hannedouche et al., 1994

- Bannister et al., 1994

- Hansson et al., 1995

- Ihle et al., 1996

- Maschio et al., 1996

Author, year Patients

- OVERALL

121

70

112

124

103

100

51

260

70

583

1594

Giatras et al, J Am Soc Nephrol, 1997

Risk Ratio & C.I.

ACE-I better ACE-I worse

1 5 20 1000.20.050.01

Pooled Risk Ratio (95% CI)

1.24 (0.55 - 2.83)

Risk of death

Pat

ient

s w

ith p

rote

inur

ia (

%)

0

30

60

< 0.5 0.5 - 3 ≥ 3

Proteinuria (g/24 h)

50 %

35 %

15 %

8

REIN CORE

Rate of GFR decline according to base-line proteinuria - Interim analysis on 177 patients

STRATUM - 1U. Prot. < 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 %

9

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)

10

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

11

RISK OF PROGRESSION TO ESRD OVER 20 MONTHS FOLLOW-UP IN PROTEINURIC CHRONIC NEPHROPATHIES

Predicted risk in 3 explicative cases

0

20

40

60

%

Serum creat mg /dl

Proteinuria g /24 h

CaxP mg2/dl2

1.2

1.9

24.3

2.1

3.9

35.1

3.5

5.2

37.2

80

12

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

13

CORRELATION BETWEEN CHANGES IN PROTEINURIA AND GFR DECLINE

1 - 3 gr/24 h

p

rote

inu

ria

*(p

erce

nt c

hang

e vs

. ba

selin

e)3

mo

nth

s

- 20

0

20

40

- 0.2 -0.3 - 0.4

Overall PlaceboRamipril

* Corrected for GFR

> 3 gr/24 h

GFR (ml/min/month)

3 years

- 0.6-0.5- 0.4-0.3 - 0.8- 0.7 0.9-0.2

- 20

0

20

40

p

rote

inu

ria

*(

perc

ent

chan

ge v

s .b

asel

ine)

3 m

on

ths

Perna et al., J Am Soc Nephrol, 2000

14

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

15

PROTEINURIA AND RISK OF DEVELOPING ESRD

Iseki et al., Kidney Int, 2003

Community-based screening in 106,177 general population

Follow-up: 17 years

16

14

12

10

8

6

4

2

0

Cum

ulat

ive

inci

denc

e of

ES

RD

(%

)

Proteinuria

Number of screened

Number of ESRD

-

86,253

185

+

10,000

38

+

4,007

55

2+

1,072

76

>3+

357

55

16

RISK OF ESRD: PREDICTIVE VALUE OF BASELINE GFR AND PROTEINURIA1993 mass screening conducted by the Okinawa General Health Maintenance Association (OGHMA)

Subjects

Inclusion criteria

Baseline parameters

Follow-up

End point

95,255

> 20 years of ageGFR > 15 ml/min

Dipstick proteinuriaCalculated GFR (Cockcroft-Gault method)

7 years

ESRD

Iseki et al., J Am Soc Nephrol, 2003

17

Proteinuria (+)

Proteinuria (-)

Number of screened

Number of ESRD1,125

8481111

7177

8006

3,453108

Number of screened

Number of ESRD21,872

2222,254

1822,312

122,229

388,667

44

Cum

ulat

ive

Inci

denc

e of

ES

RD

per

1,00

0 sc

reen

ed in

7 y

ears

GFR, ml/min/1.73m2

0

20

40

60

80

15.0-57.1 57.2-77.6 77.7-102.6 ≥102.7 Total

Fig3

Proteinuria (+)

Proteinuria (-)

18

EFFECTS OF LOSARTAN ACCORDING TO RACE:Post-hoc analyses of the RENAAL study

Asian

Black

White

Hispanic

Other

Overall

Primary end point (Doubling s. creat, ESRD or death)

252

230

734

277

19

1,261

n°Region

0.5 0.750.25 1.0 1.25 1.5

Losartan better Losartan worse


p

0.024

0.94

0.07

0.99

0.76

0.18

The whole effect of Losartan was fully driver by Asian patients

19

1-YEAR PROTEINURIA REDUCTION IN TYPE 2 DIABETICS ENROLLED IN THE RENAAL STUDY ACCORDING TO RACE

-20

-10

-15

-5

0

Med

ian

(I.Q

. ran

ge)

prot

einu

ria

redu

ctio

n vs

bas

elin

e (

%)

-19 (-56 to 36)

ASIAn = 252

p = 0.03 (ANCOVA)

Non-ASIAn = 1,261

-9 (-51 to 40)

20

Asian

Non Asian

Reduced proteinuria

YES

NO

YES

NO

YES

NO

NO

NO

Outcome improved

Risk reduction (95 % C.I.)

-25 1 25 50 75

Decreased risk Increased risk

-50-75

0.016

0.27

0.59

0.35

pBaseline proteinuria

(alb/creat g/g)

1.535

1.167

21

BASELINE CHARACTERISTICS OF ASIAN AND NON-ASIAN PATIENTS OF RENAAL STUDY

Asian(257)

60+7

102+11

25+4

Non-Asian(1256)

60+7

106+11

31+5

p

0.72

<0.005

<0.0001

Age (yrs)

MAP (mmHg)

BMI (Kg/m2)

22

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

23

0,10 ml/min/month

24

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)

16 patients with stable GFR

Remission Regression

10 patients with increasing GFR90

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

GF

R (

ml/m

in/m

on

th)

25

Pro

tein

uria

red

uctio

n vs

pr

e-br

eakp

oint

val

ues

(%)

Remissionn = 16

RELATIONSHIP BETWEEN REMISSION/REGRESSION AND POST-BREAKPOINT CHANGES IN PROTEINURIAPost hoc analyses of the REIN study

Regressionn = 10

- 40

0

- 20

- 60

-31 %

-52 %

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

26

0

10

20

30

40

50

0 6 18 30 36 48 5412 24 42

*

GF

R (

ml/1

.73

sq

m)

Y= 0.0092x - 0.6033x2 + 45.586

Y1 = - 0.3291x + 44.794 Y2 =0.387x + 19.677

* p (y1 vs y2 ): < 0.01 (F-test)

months

REGRESSION OF THE DISEASE IN PATIENTS ON CONTINUED RAMIPRIL

27

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

28

Intensify blood pressure control

Up-titrate ACE inhibitor dose

Combine with other antiproteinuric agents

Vasopeptidase inhibitors

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

CAN WE DO BETTER?

29

* No correlation between proteinuria and BP changes

THE EFFECT ON PROTEINURIA AND BLOOD PRESSURE OF INCREASING DOSES OF ACE INHIBITORS

v

s. n

o tr

eatm

ent

(%)

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

30

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

31

LDL Cholesterol

Serum Albumin

Lisinopril dose (mg/day)

Ch

ang

es

vs. b

asa

l (%

) + 40

+ 30

+ 20

+ 10

0

0 10 20 30 40 10 0

- 10

- 20

- 30

EFFECTS OF UP-TITRATING LISINOPRIL IN MEMBRANOUS NEPHROPATHY

Ruggenenti et al., Circulation, 2003

32

DUAL RENIN-ANGIOTENSIN SYSTEM BLOCKADE IS HIGHLY EFFECTIVE TO IN NON-DIABETIC PROTEINURICS

Laverman et al., Kidney Int, 2002

9 non-diabetic renal patients (6 weeks treatment per dose)

Cha

nge

of p

rote

inur

ia (

%)

-100

-75

-50

-25

0

0 10 20 40

0 50 100 150 50 - 150

10 - 40

Losartan

LisinoprilCombined

33

-70

-60

-50

-40

-30

-20

-10

0

10

24 hrs Uprot excretion

MAP

VALSARTAN(160 mg/day)

BENAZEPRIL(20 mg/day)

BENAZEPRIL + VALSARTAN

(10 + 80 mg/day)

p = 0.002

p = 0.022

p = 0.024

Per

cen

t ch

ang

e fr

om

bas

elin

e

EFFECTS ON PROTEINURIA OF 8 WEEKS COMPARABLE BLOOD PRESSURE CONTROL ACHIEVED BY COMBINED THERAPY IN 23 PATIENTS WITH CHRONIC NON-DIABETIC NEPHROPATHIES

Campbell et al., 2002

34

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

22 30 38 46 54 62 70

0.01

0.1

1.0

22 30 38 46 54 62 70

Basaline

Benazepril + Valsartan

Molecular radius (Å)

De

xtr

an

Fra

cti

on

al

Cle

ara

nc

e

Baseline

Valsartan***

**

**

**

**

**

*

**

**

**

**

**

*

***

****

**

**

**

**

**

*

*

**

Campbell et al., 2002

22 30 38 46 54 62 70

Baseline

Benazepril **

*

35

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

36

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

**

*

37

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. HOSTETTERNational Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda, Maryland

38

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


39

Uri

nar

y pr

ote

in e

xcre

tion

(g

/24

hour

s)

Se

rum cre

atin

ine

(mg/dl)

months

FULL RESPONDERS (n=19)

- Full remission of nephrotic syndrome (U.prot. <1g/24 h) - Stable s. creatinine over 4 years

0 10 20 30 40 500

1

2

3

4

5

- 10

Remission clinic

0

2

4

6

8

40

Uri

nar

y pr

ote

in e

xcre

tion

(g

/24

hour

s)

Se

rum cre

atin

ine

(mg/dl)

PARTIAL RESPONDERS (n=7)

- Partial remission of nephrotic syndrome- s. creat increase < 0.2 mg/dl/year

Remission clinic

0

1

2

3

4

5

-10 0 10 20 30months

0

2

4

6

8

40

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)


REMISSION CLINIC

42

OUTCOMES OF 160 TYPE 2 DIABETICS WITH MICROALBUMINURIA ACCORDING TO MULTIFACTORIAL OR CONVENTIONAL THERAPY

Gaede et al., N Engl J Med, 2003

Multifactorial therapy better

Multifactorial therapy worse

Fatal and non-fatal CV events

Nephropathy

Retinopathy

0.0 0.5 1.0 1.5

Relative risk (95 % C.I.)

2.0

43

When to start, why never stop

44

0

40

50

70

Inci

den

ce o

f E

SR

D (

%)

Lowest(10.5 - 32.6 ml/min)

Middle(32.6 - 50.8 ml/min)

Highest(50.8 - 101.0 ml/min)

INCIDENCE OF ESRD IN 352 PATIENTS WITH PROTEINURIC, CHRONIC NEPHROPATHIES ACCORDING TO TREATMENT AND TERTILES OF BASAL GFR

60

30

20

10

60.0 %

40.4 %

21.4 %

13.4 % 10.9 %

0.0 %

p < 0.05

p < 0.01

Co

nv

enti

on

al

Ra

mip

ril

Ruggenenti et al., J Am Soc Nephrol, 2002

45

Hariprasad et al., Am J Kidney Dis, 2002

Co

sts

save

d (

$ b

illio

n)

- 10 % - 30 %0

10

20

30

40

50

60

70

18,56

60,61

* Predicted for patients with basal GFR ≤ 60ml/min

GFR reduction*

65,000

50,000

35,000

Pre

vale

nce

2000 2010

55,000

60,000

45,000

40,000

2005

661,330

466,438

ESRDPrevalence projections

7.56

-30 %

Predicted GFR

(ml/min/yrs)

615,767

-10 %

1998 - 2010PREDICTED ESRD PREVALENCE AND CUMULATIVE SAVINGS FOR DIFFERENT DEGREES OF GFR REDUCTIONS

46

GFR DECLINE ACCORDING TO DIFFERENT UNDERLYING RENAL DISEASE

Ruggenenti et al., Am J Kidney Dis, 2000

GF

R (

ml/

min

/mo

nth

)

0

0.2

0.4

0.6

0.8

1.0

1.2

0.53±0.09

0.31±0.07

Primary Glomerular Disease

0.55±0.13

0.36±0.09

IgA Nephropathy

0.49±0.11

0.31±0.09

Nephrosclerosis

ConventionalRamipril

% GFR reduction vs control

-42 -35 -37

47

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 -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

48

Statin

Aspirin

ACE inhinitors

The superpill could be valuable also for patients with chronic nephropathies to limit both renal and cardiovascular events

49

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

50

So far, treatment of renal patients has been aimed to limit or prevent progression to ESRD

51

ANNUAL ESRD AND MORTALITY IN TYPE 2 DIABETICS WITH OVERT NEPHROPATHY

Adler et al., Kidney Int, 2003

0

20

25

15

(%)

10

5

ESRD

*

Estimate from the °UKPDS and the *RENAAL studies

Mortality

°

?

52

Preventing nephropathy is more important than retarding progression

PROJECTED CHANGES OF ISCHEMIC HEART DISEASE MORTALITY WORLDWIDE (1990 to 2020)

DEVELOPINGCOUNTRIES

DEVELOPEDCOUNTRIES

0500

100015002000250030003500400045005000

1990 2020Yusuf et al. Circulation 2001

Deaths (x 1000)

54

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

55

However, lack of access to essential drugs is a most striking aspect that underlines dramatically the existence of two different world

56

COST OF 1 YR OF THE PROJECT $ 6,200COST PER PATIENT $ 0.27PER CAPITA HEALTH EXPENDITURE $ 7.7IN INDIA

THE KIDNEY HELP TRUST PROJECT IN INDIA

Mani, Kidney Int, 2003

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

Patients with high blood pressure, diabetes or kidney diseases were put on cheap medications and followed

India

Tamil Nadu

---

57

The community programme of mass screening and free drug therapy, reported from India would not be sustainable if replicated across the whole of India

58

STARTING TO WORK FOR A LARGE-SCALE PREVENTION PROGRAM OF ESRD IN MOLDOVA

Health Authorities

Mario Negri Institute

Moldova Society of Nephrology

Igor Codreanu

ISN-COMGAN

Activation of a 4 yr program

4,762,000 population

Chisinau

Bergamo

MOLDOVA

Network between existing health care structures under the coordination of the Republican Clinical Hospital Chisinau

Large--scale screening

Intervention treatment

Continuous education

33,700 Km2

Income per month: 70 $

59

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

60

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


61

THE EFFECT OF RAMIPRIL TRIALS ON ACE INHIBITOR PRESCRIBING IN ONTARIO (CANADA)

REIN, HOPE

All ACE inhibitors

Ramipril

62

63

0

20

10

%

5

TelecomPharmaceutical

PERCENT PROFIT OF TOP COMPANIES IN EACH SECTOR

Fortune 500, 2000

15

Airlines Chemicals Automobiles

18,6

11,7

5,7 5,1

3,5

64

0

30

20

Pe

rce

nt o

f in

com

e

10

ResearchMarketing

PHARMACEUTICAL COMPANIES

Year 2000

Fortune 500, 2000

65

Pre-clinical studies

Infrastructures

Expertise - physicians - nurses - other professionals

Angell, N Engl J Med, 2000

INVESTMENT OF PUBLIC INSTITUTIONS ON INNOVATIVE DRUGS

66

It is no unlikely that the pre-clinical research could account for as much as 20 to 25% of a company’s research budget

Gerth and Stolberg, New York Times, 2000

67

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

68

A GLOBAL FUND FOR KIDNEY DISEASE

69

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

70

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

71

The one % solution:

Compassionate capitalism benefits the shareholders, the employees and the needy people

Marc Benioff, Salesforce

CORPORATE SOCIAL RESPONSIBILITY

1 % of equity1 % of profit1 % of employees’ paid hours are devoted to philanthropy

72

73

Helping patients of a less developed country is a way to thank the contribution of so many volunteers

74

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

75

76

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

77

BASELINE PROTEINURIA PREDICTS THE RESPONSE TO RAS BLOCKADE Post-hoc analyses of the RENAAL study

> 1.25

< 1.25

Overall

Primary end-point(doubling, ESRD or death)

757

756

1,513

n°Alb/creat ratio (g/g)

0.5 0.75 1.0 1.25 1.5


78

LESS NEED OF DIALYSIS FOR NON-DIABETIC AND DIABETIC RENAL DISEASE WITH RENIN-ANGIOTENSIN SYSTEM BLOCKADE

Re

lativ

e r

isk

(%)

- 50

RENAAL(n = 1,513)

- 28 %

REIN(n = 352)

- 48 %

- 40

- 30

- 20

- 10

0

IDNT(n = 1,715)

- 20 %

CAPTOPRIL(n = 409)

- 45 %

79

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

80

Inci

den

ce o

f E

SR

D (

%)

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)

0

40

50

30

20

10

Pla

ce

bo

Lo

sart

an

S. Creatinine (mg/dl)

GFR (ml/min)

2.1 - 3.6

19 - 34

1.6 - 2.0

35 - 44

0.9 - 1.5

45 - 77

81

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)

25

20

15

10

5

0

Inci

dence

(%

)

13.4

9.011.0

19.3

11.3

21.3

p < 0.003

Lowest Middle Highest

TERTILES

p < 0.01

Pla

ce

bo

Lo

s

2.1 - 3.6 1.6 - 2.0 0.9 - 1.6S. creat

82

400

200

100

300

0U

rinar

y pr

otei

n ex

cre

tion

(mg/

24 h

)0 4 8 12

Co

ntr

ol

Dia

bet

es

months

**

*

0.10

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

Por

e r

adi

i dis

trib

utio

n

0 20 30 40 50 60

Pore radius (Å)

10

Diabetic

Control

P GC

63mmHg

53mmHg

Remuzzi et al., J Am Soc Nephrol, 1993

83

0

-2

-4

-6

-8

-10

-12

-14

GF

R (

ml/m

in/y

ear)

95 98 113110107104101 119116

130/85 140/90 Untreated HTN

r = 0.69; p < 0.05

MAP (mmHg)

Parving et al., Br Med J, 1989Viberti et al., JAMA, 1993Hebert et al., Kidney Int, 1994Lebovitz et al., Kidney Int, 1994Bakris et al., Kidney Int, 1996Bakris et al., Hypertension, 1997

Klahr et al., N Engl J Med, 1993Maschio et al., N Engl J Med, 1996GISEN Group, Lancet, 1997

Bakris et al., Am J Kidney Dis, 2000

Diabetes Non-diabetes

84

ACHIEVED BLOOD PRESSURE CONTROL IN MAJOR TRIALS ON NEPHROPATHY TYPE 2 DIABETES

Trial SPB/DBP (mmHg) Study drug

RENAAL

IDNT

IRMA

142/74

142/84

144/77

Losartan

Irbesartan

Irbesartan

85

CHINA

In the 2010Diabetes 30 millions

High blood pressure/chronic renal disease 80 millions

Need of dialysis 1 million

86

ANGIOTENSIN II PARTICIPATES TO THE DEVELOPMENT OF GLOMERULAR CAPILLARY HYPERTENSION

Acute infusion of Ang II in normal rats raises intraglomerular capillary pressure

Following 5/6 nephrectomy in rats endogenous Ang II local activity increases

Myers et al., Circ Res, 1975

Mackie et al, Kidney Int, 2001

87

ESRD

0 12 24 36 48

Months

% w

ith e

vent

0

10

20

30

p=0.002

Risk Reduction: 28%

P

L

- 1513 type 2 diabetes

- Age 31-70 years

- Alb/Cr ratio >300 mg/g,

- S Creat 1.3-3.0 mg/dL,

RENAALReduction of Endpoints in NIDDM with the AII Antagonist Losartan

88

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

89

THE PROGRAMS OF PREVENTING RENAL DISEASE PROGRESSION WORLDWIDE

The funding of such programs is probably on the top of list of the difficulties

90

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

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

92

EFFECTS OF LOSARTAN ACCORDING TO THE GEOGRAPHIC AREA:Post-hoc analyses of the RENAAL study

North America

Europe

Latin America

Asia

Overall (but Asia)

Primary end point (Doubling s. creat, ESRD or death)

687

295

274

257

1,256

n°Region

0.5 0.750.25 1.0 1.25 1.5

Losartan better Losartan worse


p

0.64

0.76

0.54

0.0008

0.34

The whole effect of Losartan was fully driver by Asian patients

93

1-YEAR PROTEINURIA REDUCTION IN ASIA AND NON-ASIA TYPE 2 DIABETICS ENROLLED IN THE RENAAL STUDY

Less events in Asia patients were associated with more (double) short-term proteinuria reduction

-20

-10

-15

-5

0

Med

ian

(I.Q

. ran

ge)

prot

einu

ria

redu

ctio

n vs

bas

elin

e (

%)

-20 (-55 to 30)

ASIAn = 257

p < 0.05 (ANCOVA)

Non-ASIAn = 1,256

-9 (-51 to 43)

94

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

95

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

96

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

97

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

98

Seru

m creatin

ine

(mg

/dl)

Pro

tein

uri

a (g

/day

)

Renal biopsy *

AZA 100

… a 22 years old women with previous diagnosis of Systemic Lupus Erythematosus

* Severe chronic glomerulopathy with no signs of disease activity

1994 1995 1996 1997 19981993

10

8

6

4

2

0

MPD

3

2

1

0

Losartan 50 100 mg/day

Hydrochlorotiazide 25 mg/day

Low sodium diet 2 g/day

Enalapril 2.5 20 mg/day

Prednisone 25 5 mg/day

1999 2000 2001 2002 2003

99

PREVENTING NEPHROPATHY WILL PREVENT CV

MORTALITY?The BENEDICTstudy

BP>140/90 mmHgNormoalbuminuria

Fatal and non-fatal CV eventsProgression to microalbuminuria

BP<120/80mhgHbA1c <7,5%

July 2003

1200 type 2 diabetics:

Main end points:

Targets:

Study End:

Run-in

Ran

do

mis

atio

n

ACE-I

ndCCB

ACE-I + ndCCB

Placebo

0 1 2 3Years

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


101

On August 30, 2003 World Trade Organization reaches agreement on generic medicines

102

IMPROVING ONLINE ACCESS TO MEDICAL INFORMATION FOR LOW-INCOME COUNTRIES

WHO helped to create the Health InterNetwork Access to Research Initiative (HINARI)

Low-income countries (GNP<$1,000) offered for free online access to a large library of important international journals

Additional countries (GNP $1,000-3,000) qualified for access to the journals at a very low price ($ 1,000 per year)

Total institutions in 100 countries (of a total of 113 eligible countries) have registered for the program

Publishers of scientific publishing have joined the Network Access to offer more than 2,300 journals and other full-text resources

69

44

47

1043

Aronson, N Engl J Med, 2004

103

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

104

The pharmaceutical industry nowadays is a very profitable enterprise, and its returns are on the average greater than those of other industries

105

RamiprilConventional

Base-line urinary protein excretion (g/ 24 hours)

Mea

n ra

te o

f G

FR d

eclin

e

(ml/

min

/mo

nth)

0.2

0.4

0.6

0.8

1.0

1.2

0

2-3 3-4.5 4.5

n=6 0 n=81 n=69

<2

n=115

RESPONSE TO ACE INHIBITION ACCORDING TO DIFFERENT LEVELS OF BASELINE PROTEINURIA

Documents

1 Giuseppe Remuzzi Prevention of progression and remission/regression strategies of chronic renal diseases: can we do better now than 5 years ago? Bellagio,