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