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?