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albuminuria
1. Albuminuria – an early sign of glomerular damage
and renal disease
Cardio-renal continuum
Risk factors
Atherosclerosis
REGRESS
Target organ damage
Asymptomatic
Target organ
damage
Symptomatic
Death
CKD
ESRD
New risk factors
1
2
3
75 %
25 %
COST
%EVENTS
The "heavyweights" of modifiable CVD risk factors
Hypertension Diabetes SmokingCholesterol
LDL HDL
Global CVD risk
Diabetes
No diabetes
CV
D d
eath
rate
(per
10,0
00 p
ers
on
-year)
250
0
200
150
100
50
Systolic blood pressure (mmHg)
< 120 120–139 140–159 160–179 180–199 200
„Double jeopardy‟: type 2 diabetes and hypertension and cardiovascular risk
Prevalence and causes of end-stage renal disease
Projection
95% CI
1986 1990 1994 1998 2002 2006 20100
100
200
300
400
500
600
700
243,524
281,355520,240
Number of dialysis patients
diabeteshypertension
RISK PREDICTION IS IMPROVED BY ADDING MARKERS
OF SUBCLINICAL ORGAN DAMAGE TO SCORE
Sehestedt T, et al.
Eur Heart J 2010; 31:883-891
CONCLUSION:
Subclinical organ damage predicted cardiovascular death
independently of SCORE and the combination improves
risk prediction
The analysis included LVMI, carotid plaques, PWV and
Albumin/creatinine ratio
The Epidemiology
Hazard ratios and 95% CIs for all-cause and cardiovascular mortality according to
spline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR)
Lancet May 18, 2010 (Published Online)
Hazard ratios and 95% CIs (shaded areas) according to eGFR (A, C) and ACR (B, D) adjusted for each other, age, sex, ethnic origin, history of cardiovascular disease,
systolic blood pressure, diabetes, smoking, and total cholesterol. The reference (diamond) was eGFR 95 mL/min/1.73 m2 and ACR 5 mg/g, respectively.
Circles represent statistically significant and triangles represent not significant. ACR plotted in mg/g.
Hazard ratios and 95% CIs for all-cause and cardiovascular mortality according to
spline estimated glomerular filtration rate (eGFR) and categorical albuminuria
Lancet May 18, 2010 (Published Online)
Shaded areas represent 95% CIs. Models included spline eGFR, categorical albuminuria, and their interaction terms as well as adjustment for age, sex, ethnic origin,
history of cardiovascular disease, systolic blood pressure, diabetes, smoking, and total cholesterol. The reference (diamond) was eGFR 95 mL/min/1.73 m² plus ACR
less than 3.4 mg/mmol (30 mg/g) or dipstick test result negative or trace. Circles represent statistically significant and triangles represent not significant.
CVD Death or Admission for HF
in Patients with CHF
All-cause Mortality
in Patients with CHF
Jackson CE et al. Lancet. 2009;374:543-550.
Mortality and CVD Endpoints by Albuminuria Status
CHARM Study
No. at risk:
Normoalbuminuria 1346 1246 1168 1099 1013 817 411
Microalbuminuria 703 592 547 487 434 326 148
Macroalbuminuria 256 209 174 153 136 100 45
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Estim
ate
d c
um
ula
tive
dis
trib
ution f
unction
Macroalbuminuria
Microalbuminuria
Normoalbuminuria
0 0.5 1.0 1.5 2.0 2.5 3.0
Time (yrs)
1348 1312 1270 1234 1170 964 492
704 657 632 589 542 421 192
256 242 229 211 195 150 64
0 0.5 1.0 1.5 2.0 2.5 3.0
Time (yrs)
0.45
0.30
0.25
0.20
0.15
0.10
0.05
0
0.40
0.35
Cumulative Incidence of Venous
Thromboembolism
Mahmoodi BK et al. JAMA. 2009;301:1790-1797.
5
4
3
2
1
00 2 4 6 8
Follow-up (yr)
Microalbuminuria
Normoalbuminuria
Cum
ula
tive incid
ence (
%)
No. at risk
Microalbuminuria 1144 1094 1047 978 861
Normoalbuminuria 7296 7222 6994 6668 5954
Log-rank P<0.001
Ninomiya T, et al. J Am Soc Nephrol 2009; On-line.
*Adjusted for age, sex, HbA1c, serum lipids, BMI, smoking, alcohol use, and study drug
Association of eGFR levels during follow-up with the risk for CV events
Ninomiya T, et al. J Am Soc Nephrol 2009; On-line.
*Adjusted for age, sex, HbA1c, serum lipids, BMI, smoking, alcohol use, and study drug
Association of albuminuria levels during follow-up with the risk for CV events
albuminuria
albumin
albuminuria
albumin
healthy blood vessel
vascular damage
3. Albuminuria – an early sign of glomerular, but also
generalized vascular damage
Age- and gender-adjusted risk to develop a cardiovascular event (defined as a fatal or nonfatal myocardial infarction or cerebrovascular accident) and to develop a renal event
(defined as an eGFR slope of more than three times the mean of the normal gender-
stratified population) in the PREVEND cohort that had at least three eGFR measurements available during 7 yr of follow-up
Gansevoort, R. T. et al. J Am Soc Nephrol 2009;20:465-468
DN = diabetic nephropathy.
Adler et al. Kidney Int. 2003;63:225-232.
Annual Transition Rates Through Stages of DN
No nephropathy
Microalbuminuria
Macroalbuminuria
Elevated plasma creatinine or
Renal replacement therapy
2.0%
(1.9% to 2.2%)
2.8%
(2.5% to 3.2%)
2.3%
(1.5% to 3.0%)
1.4%
(1.3% to 1.5%)
3.0%
(2.6% to 3.4%)
4.6%
(3.6% to 5.7%)
19.2%
(14.0% to 24.4%)
Schematic presentation of the decline in GFR over years in a patient with albuminuria and in a patient with normal urinary albumin excretion
Gansevoort, R. T. et al. J Am Soc Nephrol 2009;20:465-468
Primary composite endpoint of the LIFE
stratified by time-varying albuminuria.
Ibsen H et.al J Hypertension 2004;22:1805
ONTARGET
Changes in UAE during the trial, from baseline to study end (ONTARGET)
Adapted from Mann et al. Lancet 2008
ONTARGET/TRANSCEND Investigators, Am Heart J (2004): 52-61
Tratamiento Inicial en
ONTARGET/TRANSCEND y HOPE
0
Uso
(%
)
70
60
50
40
30
20
10
ONTARGET
TRANSCEND
HOPE
IECA Estatinas
Inhibidores ECA/Estatinas
Final del Estudio
METHODS
• We have reviewed the evolution of albuminuria
in 1433 patients (mean age 60.5 years; 50.3%
male), arriving in our unit as a consequence of
arterial hypertension with varying degrees of
associated cardiovascular risk factors.
• All had in common the existence of previous
therapy with an ACEi or an ARB for a minimum
of two years before arrival in the Unit.
• The follow-up period was maintained for at least
3 years time.
Albuminuria evolution (Rate in %)
Total p=0.019 (Y3 vs Baseline)
DM No p=0.024 (Y3 vs Baseline)
DM Yes p=0.041 (V3 vs Baseline)
Basal p=0.021 (DM Yes vs DM No)
Year 1 p=0.001 (DM Yes vs DM No)
Year 2 p=0.008 (DM Yes vs DM No)
Year 3 p=0.001 (DM Yes vs DM No)
6,7
9,1
1110,5
5,2
6,8
8,6
7,6
7,3
11,2
9,8
15
0
2
4
6
8
10
12
14
16
18
20
Baseline Year 1 Year 2 Year 3
Total DM No DM Yes
Table 5. 5 Albuminuria Groups
Basal Year 1 Year 2 Year 3 p
Total
Normal
High-Normal
Micro
Proteinuria
970 (67.7)
171 (11.9)
234 (16.3)
58 (4.0)
862 (60.2)
213 (14.9)
267 (18.6)
91 (6.4)
754 (54.1)
256 (18.4)
291 (20.9)
94 (6.7)
766 (54.9)
223 (16.0)
302 (21.6)
104 (7.5)
0.004
No DM
Normal
High-Normal
Micro
Proteinuria
906 (70.0)
148 (11.4)
198 (15.3)
43 (3.3)
789 (63.0)
184 (14.7)
217 (17.3)
62 (5.0)
669 (56.1)
222 (18.6)
235 (19.7)
67 (5.6)
682 (58.2)
184 (15.7)
238 (20.3)
67 (5.7)
0.005
DM
Normal
High-Normal
Micro
Proteinuria
64 (46.4)
23 (16.7)
36 (26.1)
15 (10.9)
73 (40.3)
29 (16.0)
50 (27.6)
29 (16.0)
85 (42.1)
34 (16.8)
56 (27.7)
27 (13.4)
84 (37.5)
39 (17.4)
64 (28.6)
37 (16.5)
0.002
p DM <0.001 <0.001 <0.001 <0.001
Occurrence of MAU during
antihypertension treatment
Redón et al. Hypertens 2002; 39: 794–98
Urinary albumin
excretion mg/24hProgressors (n=22)
Non-progressors (n=165)
Baseline 1
(187)
2
(135)
3
(105)
4
(72)
Years of follow-up
0
50
100
150
200
250
(n)
Factors related to occurrence of MAU
during antihypertensive treatment
Redón et al. Hypertens, 2002
Slope of regression
lines over time
UAE Uric acid
SBP DBP
Glucose
p<0.001
p<0.03
p<0.05
p<0.03
Progressors (n=22)
Non-progressors (n=165)
-6
-4
-2
0
2
4
6
22
Can Microalbuminuria be
Prevented?
Studies of BP Lowering and RAS Inhibition
Systolic
Blood Pressure in Hypertensive Type 2 DM
With Normoalbuminuria
70
80
90
100
110
120
130
140
150
160
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Diastolic
Art
eri
al blo
od p
ressure
(m
m H
g)
Follow-up (mo)
Trandolapril
Verapamil
Trandolapril plus verapamil
Placebo
Ruggenenti P et al. N Engl J Med. 2004;351:1941-1951.
The BENEDICT Study
0 6 12 18 24 30 36 42 48
Risk of Microalbuminuria in Type 2 DM
with Hypertension and Normoalbuminuria
Ruggenenti P et al. N eEngl J Med. 2004;351:1941-1951.
The BENEDICT Study
0
5
10
15
Cu
mu
lative
in
cid
en
ce
of
mic
roa
lbu
min
uria
(%
)
Follow-up (mo)
301
300
254
229
237
214
224
203
207
187
198
176
188
164
149
136
104
89
No. at risk
Trandolapril
Placebo
Placebo
(30 events)
Trandolapril
(18 events)
A.F. (95 % CI) = 0.47 (0.26 - 0.83)
P=0.01
0 6 12 18 24 30 36 42 48 54
Preventing Left Ventricular Hypertrophy by ACEi
in Hypertensive Type 2 DM Patients
Ruggenenti et al. Diabetes Care. 2008;31:1629-1634.
A prespecified analysis
No. at risk
ACEI NO 376 375 361 324 309 241 221 107 96 29
ACEI YES 423 422 409 473 367 303 284 131 127 50
Patients
with E
CG
-LV
H (
%)
15
10
5
0
ACEi No
ACEi Yes
Months
HR (95% CI): 0.34 (0.18–0.65)
P=0.0012
The BENEDICT Study
Me
an
blo
od
pre
ssu
re (
mm
Hg
)
Follow-up (mo)
Placebo
Perindopril-indapamide
Systolic
Δ 5.6 mm Hg (95% CI 5.2–6.0)
P<0.0001
R 6 12 18 24 30 36 42 48 54 60
75
85
95
105
115
125
65
135
145
155
165
Diastolic
Δ 2.2 mm Hg (95% CI 2.0–2.4)
P<0.0001
145
81
Effect of “Add-on” Fixed Dose Combination of
Perindopril (8 mg/od) and Indapamide (1.25 mg/od)
vs Placebo on BP in 11,140 Patients With Type 2 DM
at High Risk of CVD
ADVANCE Collaborative Group. Lancet. 2007;370:829-840.
ADVANCE Collaborative Group. Lancet. 2007;370:829-840.
Effect of Perindopril-indapamide Combination on
Risk of Death, Macro- and Microvascular Events,
and Renal Events in Type 2 DMNo. (%) of patients
with event
Favors
perindopril-
indapamide
Favors
placebo
Relative risk
reduction
(95% CI)
Perindopril-
indapamide
(n=5569)
Placebo
(n=5571)
Combined 861 (15.5%) 938 (16.8%) 9% (0 to 17)
Macrovascular 480 (8.6%) 520 (9.3%) 8% (-4 to 19)
Microvascular 439 (7.9%) 477 (8.6%) 9% (-4 to 20)
All Deaths 408 (7.3%) 471 (8.5%) 14% (2 to 25)
Cardiovascular death 211 (3.8%) 257 (4.6%) 18% (2 to 32)
Total Renal Events
Total renal events 1243 (22.3%) 1500 (26.9%) 21% (15 to 27)
New or worsening nephropathy 181 (3.3%) 216 (3.9%) 18% (-1 to 32)
New microalbuminuria 1094 (19.6%) 1317 (23.6%) 21% (14 to 27)
0.5 1.0 2.0
Hazard ratio
Baseline Characteristics of Patients Randomly Assigned to Study Drugs.
Ruggenenti P et al. N Engl J Med 2004;351:1941-1951.
Incidence of Microalbuminuria in Diabetic Patients
With Normoalbuminuria by Treatment Group
Direct-renal Study
Bilous et al. Ann Intern Med. 2009;151(1): e-publication.
0
0.10
0.15
0.05
Time from randomization (yrs)
Candesartan
Placebo
No. at risk
Placebo 2618 2410 2247 2092 1754 526 15
Candesartan 2613 2426 2278 2150 1793 540 13
Cum
ula
tive p
roport
ion
HR (95% CI) = 0.95 (078-1.16)
P=0.60
0 1 2 3 4 5 6
Primary endpoint: Time to Onset of MicroalbuminuriaSub-population with BP >140/90 mmHg and/or anti-HTN treatment
Hypertensive patients
HR: 0.770; 95.1%CI: 0.630 to 0.941;
p-value: 0.0104
Risk reduction in favour of OM
40 mg: 23%
Kaplan Meier curve for the cumulative proportion of patients with adjudicated primary efficacy endpoint:
microalbuminuria during the double-blind period; Restricted Full Analysis Set (double-blind period)
Total ROADMAP population
HR: 0.774; 95%CI: 0.624 to 0.960;
expl. p-value: 0.0199
Risk reduction in favour of OM
40 mg: 23%
36
Association of estimated glomerular filtration rate and albuminuria with all-cause and
cardiovascular mortality in general population cohorts: a collaborative meta-analysis
Conclusions
Lancet May 18, 2010 (Published Online)
• eGFR less than 60 mL/min/1.73 m2 and ACR 1.1
mg/mmol (10 mg/g) or more are independent
predictors of mortality risk in the general
population.
• This study provides quantitative data for use of
both kidney measures for risk assessment and
definition and staging of chronic kidney disease.
Prevent CKD
Prevent ESRD
Prevent
Microalbuminuria
Prevent
Stroke/CVD
Prevent
CVD/Stroke
Hypertension Diabetes
Micro-
albuminuria
Chronic Kidney
Disease
OBJECTIVES:
• BP <130/80 mmHg (<125/75 mmHg if U/prot >1
g/24h) with ACEi, ARBs, CCB’s, diuretics
• Start with 2 drug-fixed dose combination if SBP
>20 mmHg and/or DBP >10 mmHg above target
• Reduce proteinuria using ACEi, ARBs, Aldo-
antagonists ndCCBs (dCCBs may increase
proteinuria)
• Slow GFR decline with ACEi, ARBs (dCCBs may
not alter GFR decline, in the absence of an
ACEi/ARB)
• Reduce CV Risk with ACEi
• ACEi, ARBs and diuretics reduce CHF, ACEi and
ARBs do not worsen IR
OBJECTIVES:
• BP goal <140/90
mmHg with ACEi,
ARBs, CCB’s
• Other CVRF control,
lipid profile
• Spot urine
albumin/creatinine ratio
OBJECTIVES:
• Intensive diabetes control
(HbA1c <6.5% or lower, PG
fasting, postprandial)
• Intensive BP control
<130/80mmHg
• RAS blockade
• Lipid profile: TChol, LDL, HDL,
TGL goals…
• Microalbuminuria - Proteinuria
• Serum creatinine, GFR
• Eye examination, ECG
OBJECTIVES:
• BP goal <130/80 mmHg
• ACEi, ARBs, combination
• Treat other CRFs
• Monitor urine Alb/Cr ratio
annually
Pre-Hypertension
IGT
Metabolic Syndrome
Prevent
Prevent
Ruilope et al, Blood Press 2007rR Ruilope et al, Blood Press 2007