Parmi les marqueurs du risque cardiovasculaire

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Parmi les marqueurs du risque cardiovasculaire
ALBUMINURIE et PROTEINURIE FONCTION RENALE
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Primary Preventive Trial GoteborgSamuelsson et
al J Hypertens 1985, 3 167
Random population sample of treated middle-aged
male hypertensives followed for more than 10
years
CVD incidence higher in - Smokers x 3 -
Cholesterol gt 7.3mmol/L x 2 - Proteinuria x
3
3
Proteinuria and Mortality in NIDDM
Normoalbuminuria
n191
Microalbuminuria
n86
Macroalbuminuria
Survival

n51
plt0.05 normo. vs. micro. and macroalbuminuria
Gall MA, et al. Diabetes 1995441303-9.
4
The proportions of participants who died during
follow-up of the DIG trial are presented by level
of estimated GFR
Shlipak MG et al. JASN 2004152195-203
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DETERMINATION OF ALBUMINURIA

• 24-h urine collection
• Night-time urine collection
• First-morning urine sample
• Express as Albumine-to-creatinine ratio
• Express as Albumin concentration

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Albuminuria
Most frequently used threshold values -20ug/min
on 24-h urine collection
Night-time urine collection -3.5 mg/mmol
creatinine on morning sample in Women 2.5
mg/mmol
in Men -20mg/L on morning
specimen ALWAYS on  Unselected   Normotensive
Subjects  ie Blood Pressure lt 140/90
Is 140/90 a normal BP in view of new
definitions? Several  normals  may present with
risk factors!!
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Women are less responsive to arterial pressure
than men WHY ?
Albuminuria
Albuminuria ug/min

LVMI m2.7
LVMI m2.7
12/2004
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ESTIMATION DE LA FONCTION RENALE
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Relationship between GFR(DTPA clearance) and age
in normotensive subjects
Slope -0.267(CI -0.075,-0.458)
Slope -1.082 (CI -1.57, -0.594)
AM 12-2006
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Cockcroft-Gault formula (mL/min)
(140- age) x weight 72 x serum creat x
0.85 if female 186 x serum creat-1.154
x age0.203 x 0.742 if female
Simplified MDRD formula (mL/min/1.73 m2)
serum creat (mg/dL) serum creatinine in
umol/L 0.0113
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Gender had no great influence on the performance
of renal function estimates. The
underestimation of GFR by CG observed in lean
subjects was reversed to overestimation in the
obese. in elderly subjects gt65 surestimation by
CG accentuated by age and the important
underestimation by MDRD was blunted MDRD was
insensitive to body mass index.
Use MDRD in the elderly CG inadequate
(overestimation) in the obese gt30 bmi but
adequate in bmi 25-30 and underestimation in bmi
lt25
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NT and HT
PP, mmHg
Age, years
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THE RENIN-ANGIOTENSIN SYSTEM AS AN ENDOCRINE
SYSTEM in the OLD CONCEPT
Angiotensinogene (liver)
RENIN(Juxtaglomerular
apparatus) Angiotensin I
Converting enzyme
Angiotensin II
Aldosterone
Systemic Vasoconstriction
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Angiotensin-converting enzyme
Chymase
dipeptidyl carboxypeptidase
monopeptidylcarboxypeptidase
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ANGIOTENSIN II
AT type 1 receptor Systemic and Renal
Vasoconstriction Na and water retention
(direct or via Aldo) Induction of Reactive
Oxygen species and inhibition of NO Glomerular
hemodynamics and Proteinuria AT1 and AT2
receptors TgF beta, Cellular Growth and
hypertrophy (effect of AT1 and - of AT2
receptors) Apoptosis Stimulation of EC matrix
synthesis and Fibrogenesis
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INHIBITION pharmacologique du SRA
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Reponses systemique et renale à 50mg
Captopril
variation PAM
variation FPR
R2 0.052
R2 0.037
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Essayer de diminuer la vitesse de progression
dune nephropathie LA NEPHROPATHY DIABETIQUE
associée au Diabete de type2
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Annual Transition Rates Through Stages of DN
No nephropathy
1.4(1.3 to 1.5)
2.0(1.9 to 2.2)
Microalbuminuria
3.0(2.6 to 3.4)
2.8(2.5 to 3.2)
DEATH
Macroalbuminuria
4.6(3.6 to 5.7)
2.3(1.5 to 3.0)
Elevated plasma creatinine or Renal replacement
therapy
19.2(14.0 to 24.4)
DN diabetic nephropathy. Adler et al. Kidney
Int. 200363225-232.
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RR
RENAAL FU 3.4 yrs IDNT FU 2.6 yrs
L vs P
Primary composite endpoints (2xScreatinine, ESRD,
death)
I vs P
I vs A
L vs P
End-stage Renal Disease
I vs P
I vs A
Losartan vs Placebo
Doubling Serum Creatinine
Irbesartan vs Placebo
Amlodipine vs Irbesartan
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Baseline Proteinuria and renal endpoints
Event rate of renal endpoints according to
baseline Albuminuria above Pugt3g/24h only 10
are event-free at 48 mos of follow up
RENAAL Study, De Zeeuw et al Kidney Int
2004652309
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EST-IL POSSIBLE DE PREVENIR LA PROGRESSION DE
NEPHROPAHY MICRO A MACRO ALBUMINURIQUE Etude
IRMA2
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Progression to DN in 590 Type 2 Hypertensive
Diabetics With Microalbuminuria (lt20ug/min in
overnight sample) Follow up of 2 years The IRMA2
study
                                               
                    Incidence of Progression to
Diabetic Nephropathy during Treatment with 150 mg
of Irbesartan Daily, 300 mg of Irbesartan, or
Placebo in Hypertensive Patients with Type 2
Diabetes and Persistent Microalbuminuria. On
placebo the change from MA to DN is 15 in
24mos Parving et al N Eng J Med 2001345870

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EST-IL POSSIBLE DE PREVENIR LA PROGRESSION DE
NEPHROPAHY NORMO A MICRO ALBUMINURIQUE Etude
BENEDICT
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Kaplan-Meier Curves for the Percentages of
Subjects with Microalbuminuria during Treatment
with Trandolapril, Verapamil or Trandolapril plus
Verapamil vs Placebo
Blood Pressure 139/81 in T group
141/82 in V group
139/80 in TV group
142/83 in P group
5.8 vs 10.9 MA 8.8 vs 8 MA
lt0.01
6 vs 11.9 MA
lt0.01
NS
Association of Verapamil and Trandolapril had no
additional favourable effect
Ruggenenti, P.
et al. N Engl J Med 20043511941-1951
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Target and achieved BP in various trials
IDNT RENAAL IRMA2
BENEDICT
Target 135/85 lt140/90
lt135/85 120/80
144/83 142/74
144/83 142/83(PL)
Placebo
Trt
140/72 (I) 140/74 (L)
143/83(I150) 139/81(V) 141/77 (A)
141/81(I300)
141/82(T)


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The COOPERATE studyLosartan 100mg vs
Trandolapril 3mg vs Combination in 336
non-diabetic nephropathy with GFR 20-70 and
Proteinuriagt0.3g/24h
Trando Los Combination
Incidence of Hyperkalemia 9.3 in Trando, 4.4
in Los and 7.9 in Combi
Nakao et al Lancet 2003361117
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ALDOSTERONE THE FORGOTTEN
CULPRIT IN CARDIORENAL DISEASE
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LALDOSTERONE au cours des traitements par IEC ou
ARA2
Diminution en phase initiale dose-dependante Puis
Reascension ulterieure - Retour AII vers son
niveau initial due au depassement du
blockage - Role de chymase - Role de
lelevation du K serique
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Angiotensin II
Aldosterone
Blood Pressure
Cellular effects Growth Factors
Fibrosis
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Angiotensin II Aldosterone
Increase EC matrix direct or via TGFBeta or PDGF
PAI-1
GLOMERULOSCLEROSIS
Plasminogen Activator Inhibitor promotes ECM
accumulation through decrease in ECM degradation
33
Sodium-induced cardiac aldosterone synthesis
causes cardiac hypertrophyTakeda et al
Endocrinology 2001 141 1901-1904
WKY rats submitted to 100mmol/kg Na chow and
water (NS) or 0.9 saline (HS) from age 3 to 11
wks
change HS vs NS LV weight
Index 20 Plasma Renin Concentration -
85 Plasma Aldo - 50 Cardiac
production Aldo 100 Cardiac Aldo Synthase
activity 100 CYP11B2 mRNA 100 Cardiac
AT1R mRNA 110
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EFFECT OF SPIRONOLACTONE (25mg od) in CKD
with moderately impaired renal function(serum
creatlt150)
Spironolactone) given on top of dual RAS blockade
in 11 patients with renal disease and BPlt140/90
28/04/2005
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Ra. Y, 54yr, nephrosclerosis
Treatment BP, mmHg S creat, µmol/l SK,
mmol/l Pu g/d LVM, g
Nifedipine40 Atenolol 50 151 /
82 172 3.6 3.63 369
Nifedipine 40 Spiro 150 158 /
98 187 4.9 1.87 313
Nifedipine 40 Atenolol 25 Spiro 75 156 /
94 173 4.7 0.84 317
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1-Increase in Pgc reliable determinant of
Proteinuria and subsequent
deterioration 2-Protection afforded if decrease
in systemic pressure combined to
fall in Pgc -explains fall GFR early after
initiation of RAS block -explains
nephroprotection -explains partial failureof
dihydropyridine CCB alone
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A ton atteint une protection renale optimale?
NON
PA optimale non atteinte quasiment jamais
lt130 Proteinurie finale gt1g/24h Peut etre
traitement trop tardif? Doses de medicaments non
optimales? Peut-on encore faire mieux?
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Have we reached optimal renal protection?

• Acei and ARB Combinations
• Very High-Dose ARB
• Ace or ARB plus Aldo Antagonists
• Renin Inhibition alone or combined??

Lack of diuretic treatment Markers of total
blockade not clearly available Renin inhibition
if better bioavailability Aldo blockade by
inhibition of synthesis? Blockade of endothelin
synthesis or receptor? Blockade of TGFbetaMAP
kinases
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OPTIMIZATION OF RENIN SYSTEM INHIBITION

• Ace ARB Combinations
• Very High-Dose ARB
• Ace or ARB plus Aldo Antagonists
• Renin Inhibition??

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Aldosterone and the progression of human chronic
renal disease
- Enhanced frequency of intrarenal cysts often
multiple located in the
medulla Torres et al, N Eng J Med
322345,1990 - Correlation between progression
CRF and urinary 17-OH corticosteroid
excretion Walser et al, Kidney Int 34859,1988
- GFR lower in patients with the highest log
PA/log PRA ratio Hene et al, Kidney Int
2198,1982 - PA independent predictor of more
rapidly declining GFR in diabetic nephropathy
Walker et al, Am J Kidney Dis, 22164,1993
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No change in BP during Spiro
Addition of Spironolactone 25mg for 24 wks
after 40 wks of treatment by Trandolapril up
titrated to 8mg in NIDDM with early DN and Aldo
escape Aldosterone Escape in 40 of the
population Sato et al Hypertension 20034164
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Mechanisms of the prohypertrophic and profibrotic
effects of dietary sodium
- Increase in BP predominant in
sodium-sensitive subjects - Increase in
circulating volume - Increase in cardiac Beta
receptor density - The tissue renin-angiotensin
system Increase in AT1R density, expression
and sensitivity Increase in induction of
cardiac ACE content and expression in heart and
aorta - Increase in tissue Aldosterone synthesis
(Takeda et al Endocrinology 2001,141
1901-1904) - Increase in Na-H exchanger activity
(Navarro-Lopez et al Eur Heart J19931418) -
Increase in Na-K ATPase activity - Direct
prohypertrophic effect of increase in
intracellular sodium - Increase mitogenesis
induced by high EC sodium concentration? -
Increase of Superoxide generation in response to
prohypertrophic substances
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Favourable effect of treatment on CV risk
Lower Albuminuria
Lower BP to Optimal Lower LVM Correct large
vessel dysfunction Minimize the decline of GFR
45
SPIRONOLACTONE IN CRF on ACEIAIIAA very risky
way to lower proteinuria!!
Patient with IgA nephropathy and CRF ( serum
Creatinine 281umol/L) S creat Pu SK Ena
20Vals 160 F 40Amlo 5 281 3.88 4.4 Aten
25 AllSpiro 25(1mo) 336 2.37 5.9
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Three circumstances of lowering of proteinuria
translating into organ protection The
Case for - Slowing progression of Diabetic
Nephropathy to ESRD
- From micro to macroalbuminuric type
II diabetes - From Normo to
Microalbuminuria
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Aldosterone in Vascular and Renal tissues
Local production of Aldosterone - In mesenteric
vessels Takeda et al, Hypertension
25170,1995 - The presence of Aldo potentiates
AII-induced VSMC hypertrophy Hatekeyama et al,
J Biol Chem 26924316, 1994 - Aldo production by
aortic EC stimulated by Angio II Brilla et al,
J Hypertens 10S75,1992 Cellular effect of
Aldo - Increase in type IV Collagen by cultured
mesengial cells in response to exogenous aldo
Wakisaka et
al, Diabetes 4395,1994 - Aldosterone-induced
Swelling of human umbilical venous endothelial
cells Oberleithner et al Hypertension
200443952 Mineralocorticoid Receptor
Expression - In the glomerulus (less than Distal
Tub Epith) (AJP 1993) - In Cardiomyocytes,
Endothelial cells and Fibroblasts (Lombes et al
Circ Res 199271503)
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0.8
The Gisen Group. Lancet 19973491857
0.4
0
-0.4
Long-term (6mo) change in GFR (ml/min/mo)
-0.8
-1.2
-1.6
-2.0
r -0.355 p 0.035
-2.4
-90
-45
0
45
90
135
180
change in urinary protein excretion rate from
baseline to 1 mo
49
RENAAL Study, De Zeeuw et al Kidney Int
2004652309
50
Proteinuria and Mortality in NIDDM
Normoalbuminuria
n191
Microalbuminuria
n86
Macroalbuminuria
Survival

n51
plt0.05 normo. vs. micro. and macroalbuminuria
Gall MA, et al. Diabetes 1995441303-9.
51
Annual Transition Rates Through Stages of DN
No nephropathy
1.4(1.3 to 1.5)
2.0(1.9 to 2.2)
Microalbuminuria
3.0(2.6 to 3.4)
2.8(2.5 to 3.2)
DEATH
Macroalbuminuria
4.6(3.6 to 5.7)
2.3(1.5 to 3.0)
Elevated plasma creatinine or Renal replacement
therapy
19.2(14.0 to 24.4)
DN diabetic nephropathy. Adler et al. Kidney
Int. 200363225-232.
52
Addition of Spironolactone 25mg for 24 wks after
40 wks of treatment by Trandolapril up titrated
to 8mg in NIDDM with early DN and Aldo
escape Aldosterone Escape in 40 of the
population Sato et al Hypertension 20034164
53
                                                 

Changes associated with treatment by 24 wks of
spironolactone (25mg od) given after 40wks of
treatment by ACE inhibitor in Type II diabetics
with early nephropathy Sato et al Hypertension
20034164
54
                                                  
                
Valsartan (160mg bid) in Heart Failure
(LVEFlt40) Changes in plasma Aldo at 4,12 and
24mos of treatment
Cohn et al Circulation 20031081306
55
Aldosterone blockade in patients with NIDDM and
Nephropathy Sato et al
Hypertension 20034164
45 pts with Type 2 DM and
microalbuminuria or overt proteinuria
and after 40wks of ACEI
Aldosterone Escape in 40 of pts
24wks
24 wks Spironolactone 25mg od
PlaceboACEI in 5pts ACEI in 13 pts
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Mrs MP Ram, 51, membranous nephropathy
SCrea 71 96 100 138
93 µmol/l SK 3.5 4.0 4.1 4.6
4.8 mmol/l
5
4
3
Proteinuria g/d
2
1
0
E 20 F 80 Irbe150
E 20 F 80 - S 25
E 20 F 40 Irbe150
Enalapril Frusemide Irbesartan Spironolactone
E 20 F 80
C
BP 127/71 101/61 106/64 96/53 104/60 PRA
2.04 37.9 84.6 ng/ml/h PAC 4.4
13.6 6.6 ng/dl
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Organisation structure/fonction
perfusion
sécrétion
filtration
excrétion
réabsorption
glomérulaire
vasculaire
tubulaire
interstitiel
58
Schéma simplifié du système rénine-angiotensine
Boehm M, Nabel E. NEJM 20023471795-7
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excess glomerular AngII in diabetic nephropathy
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The renin-angiotensin system (RAS) in the heart
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RAS in the brain
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1-Increase in Pgc reliable determinant of
Proteinuria and subsequent
deterioration 2-Protection afforded if decrease
in systemic pressure combined to
fall in Pgc -explains fall GFR early after
initiation of RAS block -explains
nephroprotection -explains partial failureof
dihydropyridine CCB alone
65
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66
NT and HT
PP, mmHg
Age, years
67
Angiotensin receptors
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POURQUOI BLOQUER LE RECEPTEUR DE RENINE

• Devrait rendre RAS totalement quiescent par
  suppression
• de AI et ses produits derives
• Inhibe lactivation par renine des protein
  kinases
• ERK 1 et ERK2 independemment de la
  generation dangio
• -Le blocage du recepteur de prorenine(90 de
  renine totale) succeptible
• de proteger contre le developpement de
• la nephropathie diabetique experimentale par
• inhibition de laugmentation de MAPK renale
• -Activation par renine de lexpression de TGFbeta
  profibrotique par mesengium meme en presence le
  block AT1

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Bias according to gender 413 Men and 437 Women
Crcl
CG
MDRD


Accentuation of underestimation by CG and MDRD in
Women
Plt0.05 versus equal renal function estimate in
men
70
Surestimation par CG accentuee par age
Inhibition par age de la sous-estimation par
MDRD
n716 n134
Crcl
CG
MDRD


Plt0.05 versus equal renal function estimate in
subjects lt 65 years of age
71
Bias according to body mass index

Crcl
CG
MDRD

Plt0.05 versus equal renal function estimate in
respectively overweight and lean subjects
72
No influence of BMI on MDRD-associated
underestimation of GFR CG adequat chez sujets
en surpoids et non-obeses
Lean Overweight Obese BMIlt25
BMI 25-30 BMI gt30 n365 n295
n190
Crcl
CG
MDRD
Plt0.05 versus equal renal function estimate in
respectively overweight and lean subjects
73
Prevalence of chronic kidney disease
Mean age 57 yr lt 65 ml/min
Ruilope L, JASN 2001
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Combination of ACEI and
losartan in normotensive, proteinuric
patients with IgA nephropathy Russo et al. Am J
Kidney Dis 199933851
Proteinuria g/d
Base
ACEI
ACEI Los 50
Los 50
Los 50 ACEI
NB No effect of doubling the dose of ACEI or
losartan alone
75
RENAAL Study, De Zeeuw et al Kidney Int
2004652309