la remissione della malattia renale cronica

1. 1
Giornate Nefrologiche Pisane
La Remissione della Nefropatia:
Speranza o Realtà
Piero Ruggenenti
Istituto di Ricerche Farmacologiche Mario Negri,
Azienda Ospedaliera Ospedali Riuniti di Bergamo,
Bergamo, Italy
Tirrenia, 7 Novembre 2009

2. 2
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

3. 3
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

4. 4
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/Crx103(µmol/l)
ΔGFR
ml/min/month
0.2
ΔGFR
ml/min/month
2
ΔGFR
ml/min/month
5

5. 5
Glomerular hypertension
Disease progression

6. 6
Mechanical strain
AngII
(pgperµgofcelllysate)
Durvasula et al, Kidney Int, 2004
Ctr
0
0.2
0.4
0.6
0.8
1.2
1.0
*
MS
0
0.5
1.0
1.5
2.0
2.5
AT1Rlevel
(adjustedfortubulin)
Ctr MS
Glomerular hypertension

7. 7 Remuzzi A. et al., J Am Soc Nephrol, 1993
P GC
63
mmHg
53
mmHg
STREPTOZOTOCIN DIABETES - RATS

8. 8
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

9. 9
DIABETES
Diabetic +
losartan
Remuzzi A. et al., J Am Soc Nephrol, 1993
Experimental

10. 10
Time (months after UNx)
Survival(%)
UNx
Control
UNx + Lis
0 3 6 9 1 2 1 5
0
20
40
60
80
100
ACE INHIBITION PREVENTS RENAL FAILURE AND DEATH IN
UNINEPHRECTOMIZED MWF/ZTM RATS
UrinaryProteinExcretion
(mg/24hrs)
Percentageofglomeruli
affectedbysclerosis
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

11. 11
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 1000.20.050.01
Risk of death
Patients had either no or 0.5-3 gr/24 hrs proteinuria

12. 12
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
0
RateofGFRdecline
(ml/min/month)
p=0.001
0.25±0.08
0.67±0.08
GISEN Group, Lancet, 1997
Conventional Ramipril
0.5
1.0
0
(ml/min/month)
Kidney survival: Conventional 54 % Ramipril 77 %
GFR decline
p=0.001
%
Conventional Ramipril
-60
-40
-20
0
40
20
P < 0.002
Change in proteinuria

13. 13
1.2
1.0
0.8
0.6
0.4
0.2
0
MeanrateofGFRdecline
(ml/min/month)
Base-line urinary protein excretion
(g/24 hours)
Ramipril
1-2 2-3 3-4.5 > 4.5
-0.2
Conventional
Ramipril
REIN
Stratum 1 Stratum 2

14. 14
REIN CORE: Stratum 1 + 2
Baseline proteinuria predicts renal disease progression
1.5
1.0
0.5
0
ΔGFR(ml/min/month)
Lowest
< 1.9
Middle
2.0 - 3.8
Highest
>3.9
Tertiles
Proteinuria (g/24 h)
95.7Kidney survival (%) 84.7* 65.8**
* p < 0.01 vs lowest; ** p = 0.0001 vs lowest and vs middle
Ruggenenti et al., Kidney Int, 1998
p = 0.0001
p = 0.007 p = 0.01
n=117 n=117n=118

15. 15
REIN CORE: Stratum 1 + 2
Predictive value of blood pressure and proteinuria
Ruggenenti et al., Kidney Int, 1998
Highest
Middle
Lowest
Lowest
Middle
Highest
0
5
10
15
20
25
30
35
40
Tertiles of baseline proteinuria
TertilesofbaselineMAP
PatientswithESRF(%)

16. 16 Perna et al., J Am Soc Nephrol, 2000
REIN CORE: Stratum 1 + 2
Short-term (3 months) changes in proteinuria predict long-term (3 years) ΔGFR
ΔGFR(ml/min/month)
- 40
- 0.40
- 0.30
- 0.50
-0.20
0 40 80
Δ proteinuria *
( percent change vs .baseline)
- 0.45
- 0.35
- 0.55
-0.25
p = 0.04
Below median
Overall
Above median
Proteinuria reduction

17. 17
Lowest
< 1.4 g/24 h
Middle
1.5 - 3.2 g/24 h
Highest
> 3.2 g/24 h
0
0.25
0.50
0.75
ΔGFR(ml/min/month)
3years
Ruggenenti et al., J Am Soc Neph, 2000
Tertiles
Proteinuria
REIN CORE: Stratum 1 + 2
Residual (3 months) proteinuria predicts disease progression
96.7Kidney survival (%) 80.2 53.8*, **
* p = 0.002 and ** p < 0.0001 vs middle and lowest respectively
P<0.0001
P=0.0008 P=0.005

18. 18
CONTINUED RAMIPRIL
GFR(ml/min/month)
Cohorts ≥ 60 months
0 18 30 42 60 months
-.16 -.13 -.11
45
40
35
30
25
20
-.10

19. 19
REGRESSION
10 patients with increasing GFR
65
60
55
50
45
40
35
30
25
20
months
-30 -20 -10 0 10 20 30
GFR(ml/min/month)
Ruggenenti et al., J Am Soc Nephrol, 1999
Break point
P = 0.01
-0.21 + 0.09 +0.49 + 0.19
Δ Proteinuria
(pre vs post break point)
%
-40
-20
-60
0
ΔGFR
(ml/min/month)

20. 20
MWF+LIS 50-60 wMWF 60wMWF 50w
Remuzzi A. et al., Kidney Int, 2006
Sclerosis was effectively reabsorbed and a consistent amount of
glomerular tissue regained normal structure
This suggests neoformation of glomerular capillary segments

21. 21 Macconi et al., 2008
Proliferating podocytes/glom
0
40
80
120
160
40W 60W LIS 40-60W
**
0
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

22. 22

23. 23
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)

24. 24
The benefits of ACEi or ARBs on renal
outcomes in placebo-controlled trials result
from a blood-pressure-lowering effect and
additional specific renoprotective actions of
these substances remain unproven

25. 25
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

26. 26
*
*
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
on ACEi or ARB had a lower incidence of events suggests
a specific renoprotection for RAS inhibitors

27. 27
g/24hours
months
0 12 2418
Proteinuria
0
1
2
3
NON-DIABETIC CHRONIC NEPHROPATHIES
6
ml/min
0 12 2418
GFR
40
50
60
70
6
months
Ramipril (n = 20)

28. 28
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
0
5
10
15
20
25
30
35
40
45
0 6 12 18 24 30 36 42 48 54
Ramipril
Ramipril +
Felodipine
SubjectswithESRD(%)
Follow-up (months)
120
140
130
Follow-upSBP
(mmHg)
R+FR
p < 0.0019

29. 29
SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)
Zoja et al., J Am Soc Nephrol, 2002
LisinoprilVehicle Lis + AII-RA
Treatment for 10 months (start treatment at 2 months)Urinaryproteinexcretion
(mg/day)
Control
0
200
400
600
800
*
Glomerulosclerosis
(%)
20
40
60
80
*
*
0

30. 30
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(g/24hours)
months
0 12 2418
0
1
2
3
6
* *
* *
* p < 0.01

31. 31
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

32. 32
g/24hours
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/min
0 12 2418
GFR
40
50
60
70
6
months
Ramipril (n = 20)
Benazepril + Valsartan (n = 20)
* *
* *
* p < 0.01

33. 33
> 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

34. 34 Mann et al., Lancet, 2008
The ONTARGET study
Renal outcomes analysis
- Only 13 % of patients with
microalbuminuria
- No patients with over proteinuria
- More BP reduction on combined therapy
- No pre-screening for ischemic
kidney diseases
- Secondary outcome analysis
Dilution effect
Functional GFR
Competitive risk

35. 35
1.2
1.0
0.8
0.6
0.4
0.2
0
MeanrateofGFRdecline
(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 > 4.50-<1
-0.2
Non-RAS inhibiting therapy
y=-0.059+0.224*X-0.010*X2
REINONTARGET
Stratum 1 Stratum 2

36. 36

37. 37
ONTARGET: components of the composite renal outcome
All deaths
Doubling s. creat
ESKD
Acute dialysis
Ramipril
(n = 8,576)
* Duration of therapy < 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

38. 38
Deaths accounted for almost 90 % of events
ESRD was not different in treatment groups
Ruggenenti and Remuzzi, Nature Reviews Nephrology, 2009

39. 39
Differences in renal outcomes were
largely driven by differences in acute
dialysis
Need for acute dialysis is a treatment-
related event
It does not reflect disease progression
Ruggenenti and Remuzzi, Nature Reviews Nephrology, 2009

40. 40
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)
Urinaryproteinexcretion
(mg/day)
Control
0
200
400
600
800
*
*
Glomerulosclerosis
(%)
20
40
60
80
*
*
*
0

41. 41
Serumcreatinine(mg/dl)
Proteinuria(g/day)
* Severe chronic glomerulopathy with no signs of disease activity
10
8
6
4
2
0
MPD
3
2
1
0
1994 1996 1998 2000 2002 2004
Renal biopsy *
AZA 100
Losartan 50 100 mg/day
Hydrochlorotiazide 25 mg/day
Low sodium 2 g/day
Enalapril 2.5
Prednisone 25 5 mg/day
20 mg/day5 mg/day
5 mg/day
2006
GFR (ml/min)
24.3
26.6
21.3 22.1
24.2
21.1
23.9 25.2

42. 42
Add and up titrate concomitant antihypertensive agents to achieve the
maximum tolerated blood pressure reduction (consider dCCBs as last choice)
Add a lipid lowering agent
Vitamin D ?
Recommend DASH* Diet
Add low-dose ACEi or ARB
Up-titrate ACEi or ARB
Add a diuretic
REMISSION CLINIC
K < 5.5 mEq/l K > 5.5 mEq/l
Ruggenenti et al., Lancet, 2001
* Dietary Approaches to Stop Hypertension, with low potassium
Add and up-titrate AII RA or ACEi
Add low-dose Aldos-antagonist
Correct metabolic acidosis
Optimize metabolic control

43. 43
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

44. 44
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, ΔGFR (CrCl), 24 h proteinuria
Ruggenenti et al., J Am Soc Nephrol, 2008

45. 45
The Remission Clinic
Ruggenenti et al., J Am Soc Nephrol, 2008
months
0
10
20
30
40
50
60
0 6 12 18 24 30 36 42 48 54 60 66 72
Cumulativeincidenceof
patientswithESRD(%)
78
Remission Clinic (patients)
Ramipril (reference-patients)
P < 0.0015

46. 46
0
10
20
30
40
50
60
0 6 12 18 24 30 36 42 48 54 60 66 72
Cumulativeincidenceof
patientswithESRD(%)
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

47. 47

48. 48
ΔGFR(ml/min/months)
Post Pre
Diabetics
p < 0.0001
Pre
Post
Non - Diabetics
Ruggenenti et al., J Am Soc Nephrol, 2008
Post
0
0.20
0.40
0.60
0.80

49. 49
RENAAL
0 12 24 36 48
Months
%withESRD
0
10
20
30
p=0.002
R.R.: 0.72 (0.58-0.89)
Placebo
Losartan
Brenner et al., N Engl J Med, 2001

50. 50 Coresh et al., Nephrology Self-Assessment Program, 2005
TYPE 2 DIABETIC ESRD INCIDENCE RATE
Changes from 1991 to 2000 (US)
0
100
200
75
50
25
20-39 50-5940-49
%
60-74 > 75 Age
-25

51. 51
Consistent antiproteinuric effect of
selective aldosterone antagonism in type 2
diabetes
Less consistent efficacy in non diabetic
chronic nephropathies
Need of close monitoring due to the high
risk of life-threatening hyperkalemia
ALDOSTERONE ANTAGONISM IN
CHRONIC NEPHROPATHIES

52. 52
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

53. 53
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%)

54. 54
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?

55. 55
00
*
*
300
200
0 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)
0 20-24 24-28 28-32
Diabetes
Diabetes +
ACEi
ACEi
ACEi
Diabetes
Diabetes +
ACEi100
200
160
120
80
40

56. 56
RENAAL
IDNT
IRMA 2BENEDICT
ESRDNormoalbuminuria Micro Macro
0 25
Duration of diabetes (years)
< 20 20 - 200 > 200UAE µg/min
13 18
2.138 patients of 8 clinical trials
from 1992 to 1995
R.R. (95 % C.I.)
1 4 160.5
Micro worse
64 256

57. 57 Ruggenenti et al., N Engl J Med, 2004
Cumulativeincidenceof
microalbuminuria(%)
0
5
10
15
0 6 12 18 24 30 36 42 48
Follow-up (months)
Placebo
(30 events)
Trandolapril
(18 events)
60
120
100
Follow-upMAP
(mmHg)
TP
80
BENEDICT Study

58. 58
FOLLOW-UP AT RENAL DISEASE PREVENTION
CLINIC (NEPAL)
* Hypertension, diabetes, proteinuria, CKD
Subjects(number)
0
4000
8000
12000
Positive*Screened
13000
4100
Follow-up: 3240 patients
After 6 to 30 months:
BP control <140/90:
Fasting glucose <120 mg/dl:
-
-
73%
63%
Reduction or stable proteinuria:- 51%
Lifestyle modifications plus low costs drugs (antihypertensives, antiproteinurics
and/or oral antidiabetics)

59. 59
90 %

60. 60
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
0
2
4
8
6
ΔmmHg
LDL chol
0
0.5
1.0
Δmmol/L
11dehydroTxB2
0
150
300
Δng/molcreat.
HCT 12.5 mg
Atenolol 50 mg
Ramipril 5 mg
Simvastatin 20 mg Aspirin 100 mg
* Comparisons vs treatments not including these agents

61. 61
1,000,000 deaths

62. 62

63. 63
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