Impact on kidney and cardiovascular outcomes Piero Ruggenenti - - PowerPoint PPT Presentation

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International Renal Meeting and Mayo Clinic Day in Sardinia

New therapies in lowering proteinuria: Impact on kidney and cardiovascular

• utcomes

Piero Ruggenenti

Clinical Research Center Aldo & Cele Daccò, Mario Negri Institute for Pharmacological Research and Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti di Bergamo Bergamo, Italy

Cagliari - May 2, 2011

2

DEVELOPING COUNTRIES DEVELOPED COUNTRIES

500 1000 1500 2000 2500 3000 3500 4000 4500 5000 1990 2020

Yusuf et al. Circulation 2001

Deaths (x 1000)

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

3

• Diabetes
• High Blood Pressure
• Chronic Renal Disease

4

PROGRESSION OF RENAL FAILURE IN 9 DIABETICS

Modified from Jones et al., Lancet, 1979

20 40 60 80 10 20 30 40 50

Time (months) 1/Cr x 10 3 (µmol/l)

∆GFR

ml/min/month

0.2

∆GFR

ml/min/month

2

∆GFR

ml/min/month

5

5

Go et al., N Engl J Med, 2004

> 60 45-59 30-44 15-29 < 15 10 20 30 40 Estimated GFR (ml/min/1.73m2) 1,120,295 adults 2.84 years follow-up

Rate of events

(per 100 person-yr)

6

RISK OF CARDIOVASCULAR EVENTS ACCORDING TO RENAL OR CORONARY ARTERY DISEASE Renal insufficiency and albuminuria Coronary artery disease

R.R. (95 % C.I.) 1 1.25 1.5 2.0 2.5 0.5 Increased risk

7

Glomerular hypertension Renal injury

Reduced number

• f nephrons

Systemic hypertension SCARRING Loss of Autoregulation

Brenner, Meyer, Hostetter, N Engl J Med, 1982

A unifying hypothesis for the progressive nature of renal disease

Diabetes

8

Mechanical strain

Ang II

(pg per µg of cell lysate) Durvasula et al, Kidney Int, 2004

Ctr

0.2 0.4 0.6 0.8 1.2 1.0

*

MS

0.5 1.0 1.5 2.0 2.5

AT1R level (adjusted for tubulin)

Ctr MS

Glomerular hypertension

9

actin ZO-1 merge Control Ang II

40 10 20 30

Albumin flux (µg/hour)

*

40 10 20 30

Albumin flux (µg/hour)

Macconi et al., Am J Pathol, 2006

10

Remuzzi A. et al., J Am Soc Nephrol, 1993

P GC 63

mmHg

53

mmHg

STREPTOZOTOCIN DIABETES - RATS

11

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 apoptosis Glomerular-tubule disconnection Increased glomerular permeability to macromolecules Proteinuria GFR loss

PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES

Remuzzi and Bertani, N Engl J Med, 1998

Podocyte loss

12

AT1 RECEPTOR MEDIATES ANG II-INDUCED ZO-1 REDISTRIBUTION AND PERMSELECTIVE DYSFUNCTION

20 µm

Control Ang II Ang II + L-158,809

*P< 0.01 vs control °P< 0.01 vs Ang II

10 20 30

Albumin flux (µg/hour) Control Ang II

*

Ang II + L-158

°

10 20 30

Albumin flux (µg/hour)

Macconi et al., Am J Pathol, 2006

13 Diabetic + losartan Remuzzi A. et al., J Am Soc Nephrol, 1993

STREPTOZOTOCIN DIABETES - RATS

14

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 apoptosis Glomerular-tubule disconnection Increased glomerular permeability to macromolecules Proteinuria GFR loss

Remuzzi and Bertani, N Engl J Med, 1998

Podocyte loss

ACEi, ARB

15

Time (months after UNx) Survival (%) UNx Control UNx + Lis

3 6 9 1 2 1 5 20 40 60 80 100

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

Urinary Protein Excretion

(mg/24 hrs)

Percentage of glomeruli affected by sclerosis

20 40 60 80 100

UNx Control UNx + Lis

100 200 300 400 500 600 700

UNx Control UNx + Lis

* ** * **

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

Remuzzi et al., Kidney Int, 1995

16

REIN CORE

Rate of GFR decline according to base-line proteinuria

• Interim analysis on 177 patients

STRATUM - 1

• U. Prot. 1-3 g/24 h

STRATUM - 2

• U. Prot.> 3 g/24 h

0.5 1.0

Rate of GFR decline

(ml/min/month) p=0.001 0.25±0.08 0.67±0.08

GISEN Group, Lancet, 1997 Conventional

0.89±0.11

Ramipril

0.39±0.10 0.5 1.0

Rate of GFR decline

(ml/min/month) p=0.001

17

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 6 12 18 24 30 80 100 36

Follow-up P=0.02

• 40
• 20

20 40 60

Reduction in Proteinuria (%) Diastolic Blood Pressure

(mm Hg) 100 90 80 70 60

Ramipril Conventional therapy

Gisen group; Lancet 1997

18

TWO CLINICAL LECTURES

ON ALBUMINURIA

Delivered at Guy s Hospital

By JAMES F. GOODHART, M.D., F.R.C.P.,

Physician to the Hospital

May 24, 1890 THE BRITISH MEDICAL JOURNAL

What is the best treatment for chronic parenchymatous nephritis? There is no drug that I know of that can be depended upon to lessen the output of albumen

19

REIN CORE

GISEN Group, Lancet, 1997 Conventional Ramipril

1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2

% patients with doubling of base- line creatinine or ESRF Mean rate of GFR decline

(ml/min/month) 70 60 50 40 30 20 10

3 - 4.5 4.5 - 7

• 7

3 - 4.5 4.5 - 7

• 7

Baseline proteinuria (g/24 h) Baseline proteinuria (g/24 h)

20

4 5 3 0 25 4 0 3 5

GFR

(ml/min/month) Ramipril Ramipril

∆ GFR = -0.44 ± 0.54 ∆ GFR = - 0.10 ± 0.50 ∆ GFR = -0.81 ± 1.12 ∆ GFR = -0.14 ± 0.87 Ramipril Conventional CORE FOLLOW-UP Ruggenenti et al., Lancet, 1998

21

CONTINUED RAMIPRIL

GFR (ml/min/month)

Cohorts > 60 months

18 30 42 60 months

• .16 -.13 -.11

45 40 35 30 25 20

• .10

22

REGRESSION

10 patients with increasing GFR

65 60 55 50 45 40 35 30 25 20 months

• 30
• 20
• 10

10 20 30

GFR (ml/min)

Ruggenenti et al., J Am Soc Nephrol, 1999 Break point P = 0.01

• 0.21 + 0.09

+0.49 + 0.19 Change in proteinuria

(post vs pre break point) %

• 40
• 20
• 60

∆GFR (ml/min/month)

23

24

MWF+LIS 50-60 w MWF 60W MWF 50W

25 Macconi et al., 2008

Proliferating podocytes/glom

40 80 120 160

40W 60W LIS 40-60W

**

5 10 15 20 25

40W 60W LIS 40-60W

No proliferating podocytes In normal Wistar rats

** °

Podocytes/glom

Lisinopril-associated increase in endothelial cells and parietal cells with podocyte phenotype

Normal range

26

27 Ruggenenti et al., THE LANCET Vol 357 May 19, 2001

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)

28

The benefits of ACEi or ARBs on renal

• utcomes in placebo-controlled trials result

from a blood-pressure-lowering effect and additional specific renoprotective actions of these substances remain unproven

29

RELATIVE RISK OF ESRD ACCORDING TO SBP DIFFERENCES BETWEEN GROUPS A meta-analysis in 73,514 patients of 127 trials (RAS inhibition vs non)

Casas et al., Lancet, 2005

Mean difference of BP (95 % CI) RR of ERSD (95 % CI)

• 6.9 mmHg (-9.1 to -4.8)
• 1.6 mmHg (-2.8 to -0.4)

+1.5 mmHg ( 0.1 to 2.9)

0.6 0.8 1.0 1.2

RAS inhibition better

30

* *

Casas et al., Lancet, 2005

• 1.6 mmHg (-2.8 to -0.4)

+ 1.5 mmHg ( 0.1 to 2.9) Pooled analysis

• 0.1 mmHg

0.6 0.8 1.0 1.2

Mean difference of BP (95 % CI) RR of ERSD (95 % CI)

RAS inhibition better

Finding that at comparable blood pressure control patients

• n ACEi or ARB had a lower incidence of events suggests

a specific renoprotection for RAS inhibitors

31

32

Design: Systematic review of randomized controlled trials Data sources: Medline, Web of Science, Embase, and the Cochrane Library databases Study selection: Studies showing the effects of using a parachute during free fall Main outcome measure: Death or major trauma defined as an injury severity score > 15

33

No randomized controlled trials of parachute use have been undertaken

34

The basis for parachute use is purely observational The parachute industry has earned billions

• f

dollars depending on belief in the efficacy of their product

35

The popularity

• f

meta- analysis may at least partly come from the fact that it makes life simpler Oversimplification may lead to inappropriate conclusions

LeLorier, N Eng J Med, 1997

36

g/24 hours months

12 24 18

Proteinuria

1 2 3

NON-DIABETIC CHRONIC NEPHROPATHIES

6

ml/min

12 24 18

GFR

40 50 60 70 6

months Ramipril

(n = 20)

37

REIN-2 study

338 patients with non-diabetic chronic renal disease and proteinuria > 1 gr/24 hour, Cr. Cl. < 70 ml/min

Ruggenenti et al., Lancet, 2005

5 10 15 20 25 30 35 40 45 6 12 18 24 30 36 42 48 54

Ramipril Ramipril + Felodipine Subjects with ESRD (%)

Follow-up (months)

120 140 130

Follow-up SBP

(mmHg)

R+F R p < 0.0019

38

SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)

Zoja et al., J Am Soc Nephrol, 2002

Lisinopril Vehicle Lis + AII-RA Treatment for 10 months (start treatment at 2 months)

Urinary protein excretion

(mg/day)

Control 200 400 600 800

*

Glomerulosclerosis

(%)

20 40 60 80

* *

39

g/24 hours months

12 24 18

Proteinuria

1 2 3

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

6

Ramipril

(n = 20)

Benazepril + Valsartan (n = 20)

* * * *

* p < 0.01 Ruggenenti et al, J Nephrol, in press

40

g/24 hours months

12 24 18

Proteinuria

1 2 3

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

6

ml/min

12 24 18

GFR

40 50 60 70 6

months Ramipril

(n = 20)

Benazepril + Valsartan (n = 20)

* * * *

* p < 0.01 Ruggenenti et al, J Nephrol, in press

41

> 20,000 patients (16,000 non diabetics) for 56 months

Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes

42

Mann et al., Lancet, 2008

The ONTARGET study Renal outcomes analysis

• 83 % of patients with

normoalbuminuria

• 4% with macroalbuminuria
• More BP reduction on combined therapy
• No pre-screening for ischemic

kidney diseases

• Secondary outcome analysis

Dilution effect

Functional GFR Competitive risk

43 1.2 1.0 0.8 0.6 0.4 0.2 Mean rate of GFR decline (ml/min/month) Base-line urinary protein excretion (g/24 hours)

Ramipril

y=0.0142+0.162*X2-0.012*X2

1-2 2-3 3-4.5 > 4.5 0-<1

• 0.2

Non-RAS inhibiting therapy

y=-0.059+0.224*X-0.010*X2

REIN

44

45

ONTARGET: components of the composite renal outcome

All deaths Doubling s.creat. ESKD Acute dialysis

Ramipril

(n = 8,576)

* Duration < 2 months Telmisartan

(n = 8,542)

Combined

(n = 8,502)

P

(combined vs ramipril)

1,014 140 33 13 993 155 31 20 1,065 166 34 28 0.14 0.11 0.85 0.02

46 Run-In Phase

Benazepril (20 mg/day) Benazepril+Valsartan (20 + 160 mg/d)

EFFECT OF ONE-MONTH ADD-ON VALSARTAN THERAPY IN 196 PATIENTS WITH CHRONIC PROTEINURIC NEPHROPATHY ON BACKGROUND BENAZEPRIL THERAPY: THE ESPLANADE TRIAL

Ruggenenti P et al, CJASN 2010

Patient Characteristics

• CKD
• Proteinuria >1 g/24h
• BP >140/90 mmHg

(or less with antihypertensive therapy

• LDL Cholesterol < 190 mg/dl
• CrCl > 20 ml/min/1.73m2

24h Proteinuria

p<0.001

• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

Changes vs Inclusion (percent)

Total Cholesterol LDL Cholesterol

(mg/dl)

• 16
• 12
• 8
• 4

p=0.002 p=0.022

47

SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)

Zoja et al., J Am Soc Nephrol, 2002 Lisinopril Vehicle Lis + AII-RA Lis + AII-RA +Cerivastatin Treatment for 10 months (start treatment at 2 months)

Urinary protein excretion

(mg/day)

Control 200 400 600 800

* *

Glomerulosclerosis

(%)

20 40 60 80

* * *

48

EFFECT OF SIX-MONTH ADD-ON FLUVASTATIN THERAPY IN 196 PATIENTS WITH CHRONIC PROTEINURIC NEPHROPATHY ON BACKGROUND DUAL RAS BLOCKADE: THE ESPLANADE TRIAL

Ruggenenti P et al, CJASN 2010

Patient Characteristics

• CKD
• Residual proteinuria >0.25 g/24h

(despite dual RAS blockade) Changes vs Randomization (percent)

• 56
• 48
• 40
• 32
• 24
• 16
• 8

p<0.001 p<0.001

Treatment Phase

(mg/dL) 24h Proteinuria Total Cholesterol LDL Cholesterol

• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

Fluvastatin NO Fluvastatin YES (80 mg/day)

49 Ruggenenti et al., JASN 2008 Before moving to the following step check serum potassium and optimize the control

• f metabolic acidiosis and hyperglycemia to minimize the risk of hyperkalemia

Add and up titrate other antihypertensive agents to achieve the maximum tolerated blood pressure reduction (consider dCCBs as last choice) Add a lipid lowering agent Vitamin D ? Low sodium diet with or without diuretics

REMISSION CLINIC

Start and up-titrate an ACEi (or an ARB)* Add and up-titrate an ARB (or an ACEi)* Dual RAS Blockade with maximum tolerated doses of ACEi and ARB

* *

50

REMISSION CLINIC

Targets:

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

51

The Remission Clinic

A matched-cohort study

• 56 patients
• 56 reference patients
• Matching
• Outcomes

CKD Proteinuria > 3 g/24 h ACEi or ARB therapy for > 6 months CKD from REIN or REIN2 Proteinuria > 3 g/24 h On Ramipril (5 mg/d) for > 6 months 1:1 Age Gender Creatinine clearance (+ 5 ml/min) Proteinuria (+ 1 g/24 h) ESRD, ∆GFR (CrCl), 24 h proteinuria

Ruggenenti et al., J Am Soc Nephrol, 2008

52

The Remission Clinic

Ruggenenti et al., J Am Soc Nephrol, 2008 months 10 20 30 40 50 60 6 12 18 24 30 36 42 48 54 60 66 72

Cumulative incidence of patients with ESRD (%)

78

Remission Clinic (patients) Ramipril (reference-patients)

P < 0.0015

53 10 20 30 40 50 60 6 12 18 24 30 36 42 48 54 60 66 72

Cumulative incidence of patients with ESRD (%)

months 78

Remission Clinic (patients) Ramipril

(reference-patients)

P < 0.0015 80

Placebo (REIN1)

(historical controls)* * Patients from REIN with CKD and proteinuria > 3 g /24 h

54

55

∆ GFR (ml/min/months) Post Pre

Diabetics

p < 0.0001

Pre Post

Non - Diabetics

Ruggenenti et al., J Am Soc Nephrol, 2008

Post

0.20 0.40 0.60 0.80

56

20 40 60 80 100 120 140 160 180 6 12 18 24 30 36 42 48 54 60 66 72

Patients without diabetes Patients with diabetes

Arterial blood pressure (mmHg) Months 6 12 18 24 30 36 42 48 54 60 66 72 Urinary protein excretion (g/24h) Months 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

57

RENAAL

Brenner et al., N Engl J Med, 2001

12 24 36 48 Months

Patients with ESRD (%)

10 20 30 p=0.002 R.R.: 0.72 (0.58-0.89)

Placebo Losartan

58

RENAAL

Brenner et al., N Engl J Med, 2001

12 24 36 48 Months

Patients with ESRD (%)

10 20 30 p=0.002 R.R.: 0.72 (0.58-0.89)

Placebo Losartan

?

59

59

SIX MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS LESS RENAL AND CARDIOVASCULAR EVENTS The RENAAL study

ESRD CV events Heart failure

0.4 0.6 0.2 0.8 1 1.2

RENAAL Study group, 2002

Hazard ratio (95 % C.I.)

Decreased risk Increased risk

60

HAZARD RATIO FOR CARDIOVASCULAR EVENTS ACCORDING TO TREATMENT AND RESIDUAL (6 MONTHS) PROTEINURIA

RENAAL study group, 2002

Hazard ratio relative to lowest proteinuria

Protein/creatinine ratio at 6 months (g/g)

CV Endpoint

1 1.01 1.02 1.03 1.04 1.05 <0.4 2.0 3.0 4.1 > 5.2

Losartan Placebo

61

Heart Failure MI Stroke CV Death

RENAAL

Secondary Composite Endpoint and Components

Losartan n=751 n 89 50 47 90 Placebo n=762 n 127 68 50 79 p 0.005 0.079 0.787 0.455 % Risk Change

• 32
• 28
• 5

+ 12

62

ANNUAL MORTALITY AND ESRD IN SUBJECTS WITH TYPE 2 DIABETES AND NEPHROPATHY

Adler et al., Kidney Int, 2003

20 25 15

(percent)

10 5

ESRD

*

Estimate from the ° UKPDS and the *RENAAL studies

Mortality

°

?

UKPDS RENAAL

63

Can we do better ?

64

64

SALT INTAKE AND RENOPROTECTION BY ACE INHIBITOR THERAPY IN PROTEINURC NEPHROPATHY: A post-hoc analysis of REIN and REIN 2 studies

• 500 patients
• Urinary Na+/creat ratio *

(mEq/g/day)

CrCl: 20-70 ml/min 1.73sqm U.P. > 1 g/day Ramipril therapy (5 mg/day) Low: < 100 n = 108 Middle: 100 - 200 n = 336 High: > 200 n = 56

* As a marker of daily sodium intake adjusted for body weight Vegter et al., 2009

65

100 80 40 20 Patients without ESRD (%) Follow-up (months) 60 12 24 36 48

Low Middle High * Sodium intake

* P < 0.05 vs middle and low

Vegter et al., 2009

66

Vegter et al., 2009

110 100 90 80

MAP (mmHg)* Sodium intake High Middle Low

70

67

Vegter et al., 2009

4 3 2 1

Urianry protein/ creatinine excretion (g/g)*

High Middle Low

110 100 90 80

MAP (mmHg)* Sodium intake High Middle Low

70 P<0.01 P<0.01

68

Unadjusted Adjusted for proteinuria

HR (95 % C.I.) for ESRD for each 100 mEq/g increase in Na+ intake

• 25
• 0.5

1 4 High sodium worse 2 High sodium better

SODIUM INTAKE AND RISK OF ESRD

Vegter et al., 2009

69

SPIRONOLACTONE (25 mg/day) IN ADDITION TO ACE INHIBITION TO REDUCE PROTEINURIA IN 8 PATIENTS WITH CHRONIC RENAL DISEASE*

Chrysostomou et al., N Egl J Med, 2001

* Antiproteinuric effect driven by 5 patients with type 2 diabetes

110 130 120 140 150

(mmHg)

Pre Post

SBP

138 + 9 100 131 + 7 1 3 2 4 5

(g/24 hours)

Pre Post

Proteinuria

3.8 + 0.8 1.7 + 0.3 p < 0.02

70

70

Mehdi et al., J Am Soc Nephrol, 2009

81 DIABETIC PATIENTS WITH MACROALBUMINURIA

20

UACR (% change vs baseline)

• 20
• 40
• 60

160 140 120 40

24-hour SBP (mmHg)

100 80 60

48 weeks Lisinopril (80 mg day) Creatinine clearance decreased with placebo or losartan, whereas did not change appreciably in the spironolactone group Placebo Losartan

(100 mg/day)

Spironolactone

(25 mg/day)

71

AN OBSERVATIONAL STUDY OF 25 PATIENTS ADMITTED IN AN INTENSIVE CARE UNIT SINCE 1994 TO 1998 FOR LIFE-THREATING HYPERKALEMIA DURING ACEi AND SPIRONOLACTONE COMBINED THERAPY

Risk factors Renal insufficiency (n=22) Age > 70 yrs (n=21) Dehydration (n=12) Worsening heart failure (n=9) Diabetes (n=5)

Dose >25 mg/d

Schepkens et al., Am J Med, 2001 2 6 4 8 10

(mEqL)

Pre Post

Serum Potassium

3.8 + 1.8 7.7 + 0.7 2 4 3 5 6

(mg/dl)

Pre Post

• S. creatinine

1.9 + 1.2 1 3.8 + 1.8 p < 0.0001 p < 0.05

72

MANAGING CARDIOVASCULAR AND RENAL RISK: The potential of direct renin inhibition

The reactive rise in renin activity may limit the effectiveness of ACE inhibitors and ARBs

Sever et al., JRAAS, 2009

73

ALISKIREN COMBINED WITH LOSARTAN IN 599 TYPE 2 DIABETICS WITH OVERT NEPHROPATHY

Parving et al., N Engl J Med, 2008

Placebo Aliskiren

(150-300 mg/d)

Comparable BP control in the two groups Similar incidence of hyperkalemia on Aliskiren (5.0%) or placebo (5.7%)

74

ANY ADDITIONAL BENEFIT FROM RENIN- INHIBITION?

More proteinuria reduction/nephroprotection as compared to dual RAS blockade with ACEi and ARBs? Less hyperkalemia or other side effects? Lower costs?

75

24-h urinary albumin excretion

(% change at 24 weeks vs baseline)

• 40
• 30
• 20
• 10

Placebo (n = 93)

P = 0.015

De Zeeuw et al, Lancet 2010

Paricalcitol 1 µg/d (n = 93) Paricalcitol 2 µg/d (n = 95)

SELECTIVE VITAMIN D RECEPTOR ACTIVATOR (PARICALCITOL) FOR ALBUMINURIA LOWERING (VITAL) IN 281 TYPE 2 DIABETIC PATIENTS WITH NEPHROPATHY ON STABLE RAS THERAPY

76

Paricalcitol1

• 1. VITAL study group, Lancet, 2010
• 2. Vogt L, et al., J Am Soc Nephrol, 2008

P=0.005 60 30 30 60

Change in UACR (%)*

Low High

Losartan2

Sodium Excretion Low High P<0.05 Sodium Excretion

OPPOSITE EFFECTS OF SALT INTAKE ON THE ANTIPROTEINURIC RESPONSE TO PARICALCITOL AND RAS INHIBITORS

77

* *

300 200

31-33 35-37 39-41

EVIDENCE THAT ACE-I HAS A DIFFERENT EFFECT ON GLOMERULAR INJURY ACCORDING TO THE DIFFERENT PHASE OF THE DISEASE AT WHICH THE TREATMENT IS STARTED

Proteinuria (mg/24h) Proteinuria (mg/24h) Perico et al., J Am Soc Nephrol, 1994

Time (weeks) Time (weeks)

20-24 24-28 28-32 Diabetes Diabetes + ACEi ACEi ACEi Diabetes Diabetes + ACEi

100 200 160 120 80 40

78

RENAAL IDNT IRMA 2 BENEDICT B

ESRD Normoalbuminuria Micro Macro

25

Duration of diabetes (years)

< 20 20 - 200 > 200 UAE µg/min 13 18

79 5 10 15 20 3 6 12 18 22 24

Follow-up (months)

Patients with macroalbuminuria (%)

PROTECTIVE EFFECT OF IRBESARTAN AGAINST PROGRESSION TO MACROALBUMINURIA IN 590 PATIENTS WITH TYPE 2 DIABETES AND MICROALBUMINURIA The IRMA-2 Trial

Parving H-H, et al. N Engl J Med 2001

Placebo Irbesartan (300 mg/d)

80

Patients with Regression to Normoalbuminuria Patients with Progression to Macroalbuminuria

Months 10 20 30 40 50 6 12 18 24 30 36 42 48 Trandolapril plus Verapamil (n=138) Trandolapril (n=143) Percent Months 6 12 18 24 30 36 42 48 10 Percent

Ruggenenti P. J Hypertension, 2010

EFFECTS ON URINARY ALBUMIN EXCRETION OF TRANDOLAPRIL ALONE OR IN COMBINATION WITH VERAPAMIL IN 281 HYPERTENSIVE TYPE 2 DIABETIC PATIENTS WITH MICROALBUMINURIA The BENEDICT B Trial

81 Patients with event (percent) 5 10 15 20 25 6 12 18 24 30 36 42 48 Months

Patients with fatal or non fatal major cardiovascular events according to regression to Normoalbuminuria

Regression (n=133) No Regression (n=148)

HR (95% CI): 0.37 (0.19-0.71), p<0.01

Ruggenenti et al, Personal Communication, 2010

100 140 Yes No 120

Follow-Up SBP (mmHg)

82

BENEDICT

ESRD Normoalbuminuria Micro Macro

25

Duration of diabetes (years) < 20 20 - 200 > 200 UAE µg/min

13 18

1,200 type 2 diabetes Treatment Follow-up Outcome Age 40 yrs Systolic/Diastolic BP > 130/85 mmHg and/or need for antihypertensive agents UAE < 20 µg/min*

• S. Creat < 1.5 mg/dl

Trandolapril 2 mg/day Verapamil 240 mg/day Trandolapril 2 mg/day + Verapamil 180 mg/day Placebo 3 years Persistent microalbuminuria > 200 µg/min* *by nephelometry in fresh urine

83 83 Ruggenenti et al., N Engl J Med, 2004

Trandolapril Cumulative incidence of microalbuminuria (%)

5 10 15 6 12 18 24 30 36 42 48 Follow-up (months)

Placebo

60 120 100

Follow-up MAP

(mmHg)

T P

80

BENEDICT Study - 2004

83

84

HR: 1.57 (95%CI: 1.03-2.41), p=0.0378 Adjusted for ACEi therapy

BENEDICT Follow-up blood pressure

Ruggenenti et al., J Am Soc Nephrol, 2006

Follow up SBP <139.16 mmHg Follow up SBP >139.16 mmHg Subjects with microalbuminuria (%)

1 2 3 4 years

20 15 10 5

5 6

ACEi NO ACEi YES

HR: 0.36 (95%CI: 0.20-0.63), p=0.0004

Subjects with microalbuminuria (%)

25 15 10 5 1 2 3 4 years 20 5 6

85

ROADMAP

ESRD Normoalbuminuria Micro Macro

25

Duration of diabetes (years) < 20 20 - 200 > 200 UAE µg/min

13 18

4,449 type 2 diabetes Treatment Follow-up Outcome Age 18 yrs A/C ratio < 35 mg/g female < 25 mg/g male One CV risk factor:

• hypertension
• dyslipidemia
• central obesity
• smoking

eGFR > 60 ml/min/1.73 sqm Olmesartan 40 mg/day Placebo 3,2 years Onset of microalbuminuria

86 86

Why a placebo arm? Why not an ACEi rather than an ARB?

87 87 Ritz et al., Diabetologia, 2010

Cumulative incidence of microalbuminuria (%)

5 10 15 6 12 18 24 30 36 42 48 Follow-up (months)

Placebo BENEDICT Placebo ROADMAP

87

88 88 Ritz et al., Diabetologia, 2010

Cumulative incidence of microalbuminuria (%)

5 10 15 6 12 18 24 30 36 42 48 Follow-up (months)

Placebo Olmesartan

ROADMAP Study - 2010

88

89 89

Cumulative incidence of microalbuminuria (%)

5 10 15 6 12 18 24 30 36 42 48 Follow-up (months)

Placebo Olmesartan

89

Trandolapril

Olmesartan: 23 % (6 % - 37%) Trandolapril: 56 % (19 % - 76 %) Hazard reduction (95 % CI)

90 90

BENEDICT

Mean age: 63

ROADMAP

Mean age: 58

Deaths (n) Placebo Study drug 4 / 603 3 / 2139 2 / 601 15 / 2380

RAS INHIBITOR THERAPY

Treatment effect in the two study cohorts was significantly different (opposite) by Mantel-Haenszel test of homogeneity (P = 0.04)

91 91

BENEDICT

Mean age: 63

ROADMAP

Mean age: 58

Deaths (n) Placebo Study drug 4 / 603 3 / 2139 2 / 601 15 / 2380

RAS INHIBITOR THERAPY

Treatment effect in the two study cohorts was significantly different (opposite) by Mantel-Haenszel test of homogeneity (P = 0.04)

Double mortality

• n olmesartan

92

10-YEAR CARDIOVASCULAR OUTCOMES IN HYPERTENSIVE TYPE 2 DIABETES PATIENTS WITH NORMOALBUMINURIA An extension of the BENEDICT trial

• 1,208 subjects
• Median follow-up
• Independent variable
• Dependent variable
• Statistical method

Age > 40 yrs BP > 130/85 mmHg UAE < 20 µg/min

• S. Creat < 1.5 mg/dl

9.1 years Baseline UAE Major CV events Fractional Polynomial Algorithm

93 93

*A fractional polynomial algorithm adjusted for: Age yr, Gender - female vs. Male, Duration of diabetes yr, History of CV disease -n/y, Smoker status n/y, Body Mass Index - kg/m2, Mean blood pressure mmHg, logarithm of HbA1c - %, logarithm of LDL-c/HDL-c ratio, Triglycerides - mg/dL, , logarithm of Serum creatinine

• mg/dL, Allocation to ACEI

n/y

1 1.5 2 2.5 3 Adjusted* Odds Ratio for CV events 1 2 3 4 5 6 7 8 9 10 11 12 13 14 UAE (ug/min)

INCREMENTAL 10-YEAR RISK FOR MAJOR CV EVENTS FOR PROGRESSIVELY INCREASING ALBUMINURIA AT INCLUSION IN 1,208 TYPE 2 DIABETES PATIENTS WITH NORMOALBUMINURIA The BENEDICT extension study

Porrini et al., Personal Comm, 2010

94 94

1 1.5 2 2.5 3 Adjusted* Odds Ratio for CV events 1 2 3 4 5 6 7 8 9 10 11 12 13 14 UAE, ug/min Porrini et al., Personal Comm, 2010

R.R. (95 % C.I.)

1 1.05 1.10 The excess CV risk is already significant for an increase in UAE from 1 to 2 g/min

0 - 1 1 - 2 UAE (µg/min)

95 95

Time to abandon microalbuminuria?

• P. Ruggenenti and G. Remuzzi

Clinical Research Centre for Rare Diseases Aldo e Cele Daccò , Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy and Unit of Nephrology, Azienda Ospedaliera, Ospedali Riuniti, Bergamo, Italy

Kidney International (2006) review

96

1 1.5 2 2.5 3 3.5 4 Adjusted* Odds Ratio for CV events 1 2 3 4 5 6 7 8 9 10 11 12 13 14 UAE, ug/min

ACE Yes ACE No

Porrini et al., Personal Comm, 2010

HR for CV events significantly lower on ACE Yes

INCREMENTAL CARDIOPROTECTIVE EFFECTS OF ACE INHIBITOR THERAPY FOR INCREASING ALBUMINURIA AT INCLUSION IN 1,208 TYPE 2 DIABETES PATIENTS WITH NORMOALBUMINURIA The BENEDICT extension study

97 Insulin resistance/endothelial dysfunction

• Obesity
• Hypertension
• Diabetes

Reduced nephron number ? Albuminuria

Unselective proteinuria

Worsening metabolic syndrome Increasing cardiovascular risk 50 100 150

GFR

(ml/min/1.73m2)

Transient hyperglycemia, hypertension ESRD Normoalbuminuria Micro Macro

25

Duration of diabetes (years)

20 - 200 > 200 UAE µg/min < 20 10 15

ACEi

?

98

5 10

Events per 100 persons/years Hoy et al., J Am Soc Nephrol, 2003

15 20 9 / 9 1 9 1 / 9 2 9 2 / 9 3 9 4 / 9 5 9 3 / 9 4 9 5 / 9 6 9 6 / 9 7 9 7 / 9 8 9 8 / 9 9 9 9 /

Conventional Perindopril

ESRD Death

A cost effectiveness analysis estimated savings of $ 800,000 AUS to $ 4,1 million at 2 years in cost of dialysis avoided or delayed

5 10

Events per 100 persons/years

15 20

ACR category at baseline (g/mol) < 34 34-99 100-199 200+

RESULTS OF A RENAL AND CARDIOVASCULAR TREATMENT PROGRAM IN AN AUSTRALIAN ABORIGINAL COMMUNITY

The Tiwi Kidney Disease Study 1990-2000 Controls Treatment cohort

99

1,000,000 deaths

100

These slides are belonging to

Piero Ruggenenti, M.D.

Mario Negri Institute for Pharmacological Research, Bergamo, Italy.

Using these slides is only authorized by mentioning the source

101

EFFECTS OF A POLYPILL (POLYCAP) ON RISK FACTORS IN 2,053 MIDDLE-AGED INDIVIDUAL FROM 50 CENTERS IN INDIA WITHOUT CV DISEASE (TIPS)

A phase II, double-blind randomized trial Polypill*

The Indian Polycap Study (TIPS), Lancet, 2009

SBP DBP

2 4 8 6

∆ mmHg LDL chol

0.5 1.0

∆ mmol/L 11dehydroTxB2

150 300

∆ ng/mol creat.

HCT 12.5 mg Atenolol 50 mg Ramipril 5 mg Simvastatin 20 mg Aspirin 100 mg

* Comparisons vs treatments not including these agents

102 KDDC COORDINATING CENTER

Centers

SERVER Unit conversion for laboratory tests (i.e: serum Creatinine

from µmol/l to mg/dl)

China La Paz, Bolivia 2165 Damanhour, Egypt, 699 Chisinau/Ialovani, Moldova 1025 Beijing, 2310 Wanzai, 739 Fuxing, 763 Guilin, 4207 Dharan, Nepal 6885

Screened subjects (20,560)

www.isn-online.org

Ulaanbatar, Mongolia 1167 Kolkata, India, 600

103

104

REIN CORE

Rate of GFR decline according to base-line proteinuria

• Interim analysis on 177 patients

STRATUM - 1

• U. Prot. 1-3 g/24 h

STRATUM - 2

• U. Prot.

3 g/24 h 0.5 1.0

Rate of GFR decline

(ml/min/month) p=0.001 0.25±0.08 0.67±0.08

GISEN Group, Lancet, 1997 Conventional Ramipril

0.5 1.0 (ml/min/month)

Kidney survival: Conventional 54 % Ramipril 77 %

GFR decline

p=0.001

% Conventional Ramipril

• 60
• 40
• 20

40 20 P < 0.002

Change in proteinuria

105

24-h urinary albumin excretion

(% change at 24 weeks vs baseline)

• 40
• 30
• 20
• 10

Placebo (n = 93)

P = 0.015

De Zeeuw et al, Lancet 2010

Paricalcitol 1 µg/d (n = 93) Paricalcitol 2 µg/d (n = 95)

SELECTIVE VITAMIN D RECEPTOR ACTIVATOR (PARICALCITOL) FOR ALBUMINURIA LOWERING (VITAL) IN 281 TYPE 2 DIABETIC PATIENTS WITH NEPHROPATHY ON STABLE RAS THERAPY

106

107

RENAAL IDNT

ESRD Normoalbuminuria Micro Macro

25

Duration of diabetes (years)

< 20 20 - 200 > 200 UAE µg/min 13 18

108

ANNUAL MORTALITY AND ESRD IN SUBJECTS WITH TYPE 2 DIABETES AND NEPHROPATHY

Adler et al., Kidney Int, 2003

20 25 15

(percent)

10 5

ESRD

*

Estimate from the ° UKPDS and the *RENAAL studies

Mortality

°

?

UKPDS RENAAL

109

A PROSPECTIVE, RANDOMIZED, OPEN LABEL, BLINDED END POINT (PROBE) TRIAL TO EVALUATE WHETHER, AT COMPARABLE BP CONTROL COMBINED THERAPY WITH THE ACE INHIBITOR BENAZEPRIL AND THE ARB VALSARTAN REDUCES PROGRESSION TO ESRD MORE EFFECTIVELY THAN BENAZEPRIL OR VALSARTAN ALONE IN HIGH-RISK PATIENTS WITH TYPE 2 DIABETES AND OVERT NEPHROPATHY The VALID study: Clinical-Trials.gov Identifier NCT 00494715

120 patients 1:1:1 randomization Follow Up Efficacy variables Type 2 diabetes (WHO criteria) Age > 40 yrs Urinary A/C ratio > 500 mg/g (on ACEi or ARB therapy) S.Creat >1.8 and <3.5 mg/dl Benazepril

(20mg/day)

Valsartan

(320 mg/day)

Benazepril + Valsartan

(10 mg + 160 mg/day)

3 years ESRD (primary) Doubling serum creatinine, ESRD or death GFR decline (iohexol plasma clearance)

110

Dual RAS blockade may reduce the need for HMGCoA reductase inhibitor therapy in patients with proteinuric nephropathy and associated dyslipidemia

111 111 Ruggenenti et al., N Engl J Med, 2004

Trandolapril Cumulative incidence of microalbuminuria (%)

5 10 15 6 12 18 24 30 36 42 48 Follow-up (months)

BENEDICT Study - 2004

111

?

112

A PROSPECTIVE, RANDOMIZED, OPEN LABEL, BLINDED END POINT (PROBE) TRIAL TO EVALUATE WHETHER, AT COMPARABLE BP CONTROL COMBINED THERAPY WITH THE ACE INHIBITOR BENAZEPRIL AND THE ARB VALSARTAN REDUCES THE INCIDENCE OF MICROALBUMINURIA MORE EFFECTIVELY THAN BENAZEPRIL OR VALSARTAN ALONE IN PATIENTS WITH TYPE 2 DIABETES AND HIGH-NORMAL ALBUMINURIA The VARIETY study: Clinical-Trials.gov Identifier NCT 00503152

1200 patients 1:1:1 randomization Follow Up Primary outcome Type 2 diabetes (WHO criteria) Age > 40 yrs BP > 130/80 mmHg Urinary A/C ratio > 7 µg/min Benazepril

(20mg/day)

Valsartan

(320 mg/day)

Benazepril + Valsartan

(10 mg + 160 mg/day)

3 years Microalbuminuria

(persistent UAE >20 µg/min in 2 of 3 urine collections)

113

TWO CLINICAL LECTURES

ON ALBUMINURIA

Delivered at Guy s Hospital

By JAMES F. GOODHART, M.D., F.R.C.P.,

Physician to the Hospital

May 24, 1890 THE BRITISH MEDICAL JOURNAL

114

What is the best treatment for chronic parenchymatous nephritis? There is no drug that I know of that can be depended upon to lessen the

• utput of albumen

115

In type 2 diabetes patients with nephrotic range proteinuria, renal changes are likely irreversible and refractory to intervention

116

SELECTIVE VITAMIN D RECEPTOR ACTIVATOR (PARICALCITOL) FOR ALBUMINURIA LOWERING IN 281 TYPE 2 DIABETIC PATIENTS WITH NEPHROPATHY (VITAL)

Patients Design Treatment Outcome 281 Type 2 diabetics on stable RAS inhibitor therapy eGFR 15 to 90 ml/min/1.73m2 U A/C ratio 100 to 3,000 mg/g PTH 35 to 500 pg/ml Multicenter, randomized, double blind, placebo-controlled Paracalcitol (1 µg/d) Paracalcitol (2 µg/d) Placebo Urinary albumin reduction at 24 weeks

VITAL study group, Lancet, 2010

117

THE VITAL STUDY

24-h urinary albumin excretion

(% change vs baseline)

• 40
• 30
• 20
• 10

Placebo (n = 93)

P = 0.053

Paricalcitol 1 µg/d (n = 93) Paricalcitol 2 µg/d (n = 95)

VITAL study group, Lancet, 2010

118 118

Future randomized trials are needed to identify levels of albuminuria below which further therapy is no longer beneficial

Ruggenenti and Remuzzi Kidney International, 2006

119 119

The 10-year cardioprotective effect

• f ACE inhibitor therapy was

appreciable in subjects with UAE at inclusion as low as 7 µg/min

120

168 GENES DIFFERENTIALLY REGULATED BETWEEN PROTEINURIC PATIENTS AND CONTROLS

Rudnicki et al., Kidney Int, 2007

Apoptosis Cell adhesion Cell proliferation/cell-cycle control Cell differentation Immune response Transport - intracellular Transport - membrane Metabolism - amino acid and protein Metabolism - lipid Metabolism - carbohydrate Metabolism - nucleic acids Metabolism - general Signal transduction Structural Transcription/translation Hemostasis Hormone binding Nucleus Membrane N° of genes 3 9 8 2 10 9 8 15 9 6 2 7 25 12 28 2 1 6 6

121

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 apoptosis Glomerular-tubule disconnection Increased glomerular permeability to macromolecules Proteinuria GFR loss

PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES

Remuzzi and Bertani, N Engl J Med, 1998

Podocyte loss

122

Remuzzi A. et al., J Am Soc Nephrol, 1993

Intracapillary Pressure 63 mmHg 53 mmHg

STREPTOZOTOCIN DIABETES - RATS

123

Glomerular hypertension

Mechanical strain Podocyte number

Durvasula et al., Kidney Int, 2004

Ang II

(pg per µg of cell lysate)

*

Pore dimension

AT1R level

(adjusted for tubulin)

Proteinuria

124

ACE-I AND RISK OF DEATH Non-diabetic chronic renal disease

Giatras et al, J Am Soc Nephrol, 1997

• 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

Risk Ratio & C.I. ACE-I better ACE-I worse Pooled Risk Ratio (95% CI)

1.24 (0.55 - 2.83)

1

5 20 100 0.2 0.05 0.01

Risk of death

Patients had either no or 0.5-3 gr/24 hrs proteinuria

125 125

ANTIPROTEINURIC RESPONSE TO DUAL RAS BLOCKADE IN PRIMARY GLOMERULONEPHRITIS A meta-analysis of 425 patients of 13 RCTs vs ACEi vs ARB

Changes in proteinuria (95 % C.I.)

• 1
• 0.5

0.0 0.5 g/24 hours Proteinuria: 0.8 - 7.9 g/24 hours Follow-up: 1.5 - 12 months Catapano et al., Am J Kidney Dis, 2008

Five patients on dual blockade prematurely withdrawn because of adverse effects (K+ : n = 1) compared to five on ACEi and two on ARBs

126 Coresh et al., Nephrology Self-Assessment Program, 2005

TYPE 2 DIABETIC ESRD INCIDENCE RATE Changes from 1991 to 2000 (US)

100 200 75 50 25

20-39 50-59 40-49 % 60-74 > 75 Age

• 25