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Nephroprotection: Actual perspective of ACE inhibitor therapy Piero Ruggenenti Mario Negri Institute for Pharmacological Research Bergamo, Italy Malaga, October 10, 2005. 1,800,000 patients with ESRD. J. Weening, G. Remuzzi, Lancet, 2005. 90 %. DIALYSIS POPULATION. GLOBAL MAINTENANCE.

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Nephroprotection: Actual perspective of ACE inhibitor therapy Piero Ruggenenti

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Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

Nephroprotection:

Actual perspective of ACE inhibitor therapy

Piero Ruggenenti

Mario Negri Institute for Pharmacological Research

Bergamo, Italy

Malaga, October 10, 2005


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

1,800,000 patients with ESRD

J. Weening, G. Remuzzi, Lancet, 2005


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

90 %


Global maintenance

DIALYSIS POPULATION

GLOBAL MAINTENANCE

TEN YEAR MEDICAL COSTS

2,500,000

1,200

$

1,000

2,000,000

800

$ ( billions)

1,500,000

600

$

1,000,000

400

500,000

200

$

0

0

1990

2000

2010

1981-1990

1991-2000

2001-2010

Lysaght, J Am Soc Nephrol, 2002


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

1,000,000 deaths


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

80

60

1/Cr x 10 3(µmol/l)

40

20

0

0

10

20

30

40

50

Time(months)

PROGRESSION OF RENAL FAILURE IN 9 DIABETICS

Modified from Jones et al., Lancet, 1979


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

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”


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

GLOMERULAR HYPERTENSION AND THE EFECT OF ACE-INHIBITORS IN EXPERIMENTAL DIABETES

Control

Diabetes

0

10

20

30

40

50

60

70

DP (mmHg)

DP = transmembrane pressure difference

Zatz et al., J Clin Invest, 1986


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

GLOMERULAR HYPERTENSION

Mechanical strain

*

1.2

2.5

1.0

2.0

Ang II

(pg per µg of cell lysate)

0.8

AT1R level

(adjusted for tubulin)

1.5

Podocyte number

0.6

1.0

0.4

0.5

0.2

0

0

Ctr

MS

Ctr

MS

Durvasula et al, Kidney Int, 2004

Pore dimension

Proteinuria

SCARRING

Riser et al., Am J Pathol, 1996


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

PODOCYTE DYSFUNCTION IN RESPONSE TO PROTEIN LOAD

Ang II

ACEi / AIIRA

Increased glomerular permeability to proteins

Proteinuria

Podocyte protein accumulation

Loss of differentiated phenotype

Cytoskeleton rearrangement

Gene activation

TGF-b

Slit diaphragm dysfunction

Prosclerosing activation of mesangial cells

Podocyte detachment

Foot process effacement

Permselective dysfunction

Permselective dysfunction

GLOMERULOSCLEROSIS

Abbate et al., Am J Pathol, 2002


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES

Renal injury

Increased glomerular permeability to macromolecules

Glomerular-capillary hypertension

Reduction of nephron numbers

Proteinuria

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


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

ACE INHIBITION PREVENTS RENAL FAILURE AND DEATH IN UNINEPHRECTOMIZED MWF/ZTM RATS

*

700

600

500

Urinary Protein Excretion

(mg/24 hrs)

400

300

200

100

**

0

Control

UNx

UNx + Lis

*

100

Control

Percentage of glomeruli

affected by sclerosis

100

80

UNx + Lis

80

(%)

60

60

40

Survival

40

20

20

**

UNx

0

0

0

3

6

9

1 2

1 5

Control

UNx

UNx +

Time (months after UNx)

Lis

* p < 0.05, **p < 0.01 vs control

Remuzzi A. et al., Kidney Int, 1995


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

REIN CORE

Rate of GFR decline according to base-line proteinuria

- Interim analysis on 177 patients

p=0.001

0.89±0.11

1.0

Rate of GFR decline

(ml/min/month)

p=0.001

1.0

0.39±0.10

Rate of GFR decline

(ml/min/month)

0.5

0.67±0.08

0.5

0.25±0.08

0

Conventional

Ramipril

0

STRATUM - 1

U. Prot. 1-3 g/24 h

STRATUM - 2

U. Prot. ≥ 3 g/24 h

Ramipril 77 %

Kidney survival:

Conventional 54 %

GISEN Group, Lancet, 1997


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

REIN CORE

Conventional

Ramipril

1.6

70

1.4

60

Mean rate of GFR decline

(ml/min/month)

% patients with doubling of base-line creatinine or ESRF

1.2

50

1.0

40

0.8

30

0.6

20

0.4

10

0.2

0

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)

GISEN Group, Lancet, 1997


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

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

70

60.0

60

50

40.4

Incidence of ESRD (%)

40

30

21.4

p < 0.01

20

Conventional

13.4

10.9

Ramipril

10

0.0

0

Middle

(32.6 - 50.8)

Lowest

(10.5 - 32.6)

Highest

(50.8 - 101.0)

GFR (ml/min)

TERTILES

Ruggenenti et al., J Am Soc Nephrol, 2002


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

EFFICACYAND SAFETYOF BENAZEPRILIN PATIENTS WITH ADVANCEDCHRONIC RENAL INSUFFICIENCY (ESBARI)

A randomized controlled trial

Patients:

Inclusion criteria:

Treatment:

Follow-up:

Outcomes

Primary:

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 death

Proteinuria

Hou et al., 2005


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

EFFICACYAND SAFETYOF BENAZEPRILIN PATIENTS WITH ADVANCEDCHRONIC RENAL INSUFFICIENCY (ESBARI)

A randomized controlled trial

100

80

Benazepril

60

Patients without doubling serum

creatinine,ESRD, or death (%)

Placebo

40

20

0

0

12

24

36

Months of follow-up

Hou et al., 2005


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

LESS PROGRESSION TO ANURIA IN 60 PERITONEAL DIALYSIS PATIENTS DURING 1-YEAR ACE INHIBITOR THERAPY

Aprospective randomized study

100

80

60

40

20

0

Placebo

Ramipril

(5 mg/day)

Target blood pressure: <135/85 mmHg

Philips et al., J Am Soc Nephrol, 2002


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

ACE INHIBITORS AND SURVIVAL OF HEMODIALYSIS PATIENTS

A retrospective analysis (1994-2000) at a single Institution

100

80

ACEi YES

n = 60

60

p < 0.0006

Cumulative survival (%)

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

Efrati et al., Am J Kidney Dis, 2002


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

Ramipril

Ramipril

4

5

D GFR = -0.44 ± 0.54

4

0

D GFR = -0.10 ± 0.50

GFR

(ml/min/month)

3

5

3

0

D GFR = -0.81 ± 1.12

D GFR = -0.14 ± 0.87

2

5

Conventional

Ramipril

FOLLOW-UP

CORE

Ruggenenti et al., Lancet, 1998


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

0,10 ml/min/month


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

Cohorts

≥ 36 months

≥ 42 months

≥ 48 months

≥ 54 months

CONTINUED RAMIPRIL

45

40

35

DGFR (ml/min/month)

30

25

-.33

-.30

-.24

-.23

-.20

-.21

-.18

-.16

-.24

-.19

-.17

20

months

0

18

30

0

18

30

42

0

18

30

42

0

18

30

42

SWITCHED RAMIPRIL

45

40

35

DGFR (ml/min/month))

30

25

-.46

-.52

-.46

-.52

-.49

-.28

-.46

-.45

-.45

-.51

-.53

20

0

18

30

0

18

30

42

0

18

30

42

0

18

30

42

months

Ruggenenti et al., J Am Soc Nephrol, 1999


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

-.10

CONTINUED RAMIPRIL

SWITCHED RAMIPRIL

Cohorts

≥ 60 months

≥ 60 months

45

40

35

DGFR (ml/min/month)

30

25

-.16

-.13

-.11

-.25

-.35

-.44

-.30

20

0

18

30

42

60

0

18

30

42

60

months

months

Ruggenenti et al., J Am Soc Nephrol, 1999


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

REGRESSION

REMISSION

10 patients with increasing D GFR

16 patients with stableD GFR

Change in proteinuria

(post- vs pre- breakpoint)

- 31 %

- 52 %

90

90

80

80

70

70

60

60

GFR (ml/min/month)

50

50

40

40

30

30

20

20

10

10

0

0

0

10

20

30

40

50

60

0

10

20

30

40

50

60

months

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)

Ruggenenti et al., J Am Soc Nephrol, 1999


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

EVIDENCE FOR GLOMERULAR CAPILLARY REGENERATION AND REABSORPTION OF SCLEROSIS AREAS

100

MWF 60 w

80

60

100

40

MWF 50 w

80

20

60

Number of glomeruli (%)

0

0

<25

25-50

50-75

>75 %

40

100

MWF 60 w + LIS

20

80

0

60

>75 %

0

<25

25-50

50-75

% sclerotic changes

40

20

0

0

<25

25-50

50-75

>75 %

Remuzzi et al., J Am Soc Nephrol, 2003


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

#1

#60

#80

#20

#1

#60

#100

#40

#80

#20

#100

#40

MWF 60 W

MWF 50 W

MWF 60 W + LISINOPRIL

#1

#60

#20

#80

#100

#40


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

Definitions of progression, remission, and regression of proteinuric chronic nephropathies

Variable

Progression

Remission

Regression

Proteinuria

Glomerular filtration rate

Renal structural changes

≥ 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


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

NON-DIABETIC CHRONIC NEPHROPATHIES

Ramipril (n = 20)

Proteinuria

GFR

3

70

2

60

g/24 hours

ml/min

1

50

40

0

0

6

12

18

24

0

6

12

18

24

months

months


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

CAN WE DO BETTER?

protein traffic

Up-titrate ACE inhibitor dose

Intensify blood pressure control

Combine with other antiproteinuric agents

Vasopeptidase inhibitors

Low-protein diet

  • - Non-dihydropyridinic Ca-channel blockers

  • Ang II receptor blockers

  • Aldosterone antagonists

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

  • C3 inhibitory agents


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

24 h Proteinuria*

M.A.P.*

y=-1.23x - 12.07

0

+20

r =-1.23; p<0.02

-10

+10

0

-20

D vs. no treatment (%)

-30

-10

-40

-20

-50

-30

-60

-30

0

5

10

15

20

0

5

10

15

20

Ramipril dose (mg/day)

Ramipril dose (mg/day)

* No correlation between proteinuria and BP changes


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

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


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

REIN-2

Patients:

Inclusion criteria:

Treatment:

Follow-up:

Outcomes:

335 subjects with non-diabetic chronic nephropathies

Proteinuria > 1 g/24 hours

Cr. 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

ESRD

DGFR (in a sub-group)


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

MEAN ARTERIAL PRESSURE IN EACH STUDY ARM

104

102

100

Ramipril

Mean arterial pressure

(mmHg)

98

Ramipril +

Felodipine

96

94

92

90

0

3

6

9

12

15

18

21

24

Months

Ruggenenti et al., Lancet, 2005


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

REIN-2

Ramipril +

Felodipine

45

40

Ramipril

35

30

25

Subjects with ESRD (%)

20

15

10

5

0

0

6

12

18

24

30

36

42

48

54

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

Ruggenenti et al., Lancet, 2005


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

Lancet, 2005

Renoprotective therapy: is it blood pressure or albuminuria that matters?

Paul E. De Jong, Dick de Zeeuw


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

A CASE-CONTROL STUDY OF SINGLE OR DUAL RAS INHIBITION IN PATIENTS WITH NON-DIABETIC CHRONIC NEPHROPATHIES

Ramipril (n = 20)

Benazepril + Valsartan (n = 20)

Proteinuria

GFR

3

70

2

60

* p < 0.01

g/24 hours

ml/min

1

50

*

*

*

*

40

0

0

6

12

18

24

0

6

12

18

24

months

months


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

COOPERATE study: results

100

Combination

Losartan

80

Trandolapril

Patients without events * (%)

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


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)

800

Treatment for 10 months (start treatment at 2 months)

600

Urinary protein excretion

(mg/day)

*

400

200

*

0

80

60

Glomerulosclerosis

(%)

40

*

*

20

*

Lisinopril

Lis + AII-RA

Lis + AII-RA

+Cerivastatin

Control

Vehicle

Zoja et al., J Am Soc Nephrol, 2002


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

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

Add AII RA or ACE i

Up-titrate AII RA or ACE i to

maximum dose

K > 5.5 mEq/l

K < 5.5 mEq/l

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


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

REMISSION CLINIC

Targets of the multidrug approach:

Blood pressure< 120/80 mmHg

Proteinuria< 0.3 g/24 h

LDL< 100 mg/dl

LDL + VLDL< 130 mg/dl

HbA1c< 7.5 % (diabetics)

Ruggenenti et al., Lancet, 2001


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

- Full remission of nephrotic syndrome (U.prot. <1g/24 h) in 25 patients

- Stable s. creatinine

5

8

Remission clinic

4

6

Urinary protein excretion

(g/24 hours)

3

Serum creatinine

(mg/dl)

4

2

2

1

0

0

24 - 50

0

6

12

18

24

- 12

- 6

months


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

- Residual proteinuria > 1g/24 h in 11 patients

Remission clinic

5

8

*

4

6

Urinary protein excretion

(g/24 hours)

3

Serum creatinine

(mg/dl)

4

2

2

1

0

0

> 24

0

6

12

18

24

- 12

- 6

months

* 2 patients progressed to ESRD


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

TYPE 2 DIABETES

FULL-RESPONDERS (n=5)

- Full remission of nephrotic syndrome (U.prot. <1g/24 h)

- Stable s. creatinine

3

8

Remission clinic

6

2

Serum creatinine

(mg/dl)

Urinary protein excretion

(g/24 hours)

4

1

2

0

0

> 24

0

6

12

18

24

- 6

months


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

TYPE 2 DIABETES

PARTIAL-RESPONDERS (n=13)

- Residual proteinuria > 1g/24 h

Remission clinic

3

8

6

2

Serum creatinine

(mg/dl)

Urinary protein excretion

(g/24 hours)

4

1

2

0

0

> 24

0

6

12

18

24

- 6

months


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

TYPE 2 DIABETES

200

Remission clinic

SBP

180

160

Responder

Non-Responder

140

(mmHg)

120

100

Responder

80

Non-Responder

60

40

> 24

0

6

12

18

24

- 6


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

Non-diabetic proteinuric nephropathies

Diabetic nephropathy

25

25

25

20

20

15

15

13

Number

Number

11

10

10

5

5

5

0

0

Non-

responders

Non-

responders

Responders

Responders

p < 0.01 non-diabetic proteinuric nephropathy vs diabetic nephropathy (Chi square test)


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

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

130

120

mmHg

g / 24h

1.0

0.5+.03

p < 0.05

100

90

80

0.5

70

Post

Pre

Post

Pre

Pechter et al., Nephrol Dial Transplant, 2003


Nephroprotection actual perspective of ace inhibitor therapy piero ruggenenti

A swimming pool for the Clinical Research Center?


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