The

Importance Of Proteinuria
as Predictor of CVD

Syafrizal Nasution
Nephrology & Hypertension Hypertension ,Dept of Internal Medicine
Medical Faculty USU /Adam Malik General Hospital, Medan

The 12th Scientific Meeting of Indonesian Society Of Hypertension (Ina SH)

23-25th February2018, Sheraton Grand Hotel.
CV : dr Syafrizal Nasution, Mked,SpPD,KG-H
I . Education
q Doctor FK USU 1994
q Internist FK USU 2007
q Magister of Internal Medicine, FK USU 2012
q Nephrology & Dialysis Course, Gold Coast Hospital, Australia 2013
q Internist Nephrologist 2015
II. Current Position
q Head of Renal & Hypertension Unit, Adam Malik General Hospital
2014
q Head of Nephrology & Hypertension Division, Dept of Internal
Medicine,FK USU 2015
 O U T L I N E
• Introduction
• Epidemiology
• Pathophysiology
• Albuminuria and Clinical Outcomes
• Reducing the Risk Associated with Microalbuminuria
•  Screening
•  Risk Stratification
•  Treatments
• Conclusion
Definition
Proteinuria is defined as an excessive excretion of any
protein or proteins into the urine

the most abundant protein found in urine in those with proteinuria is

albumin which normally filtered by the glomerulus and reabsorbed in
the proximal tubule of the kidney; therefore, only minute quantities of
albumin are normally present in the urine

When urine albumin is persistently present in excessive

amounts, it is a sign of potentially serious CVD
Classification of Urinary Albumin Excretion
 Comparison of Proteinuria and Albuminuria
Proteinuria Albuminuria
Definition All Proteins Albumin Only

Detected by routine Yes No
dipstick

Method of measurement Protein:creatinine ratio Albumin:creatinine ratio

Signifies intrinsic renal Yes No
disease

Signifies increased Yes Yes
cardiovascular event risk
Definition & Clinical Significance of Abnormal Albumin Excretion

Microalbuminuria Macroalbuminuria
Definition Urine albumin:creatinine Urine albumin:creatinine
ratio 30–299 mg/g ratio ≥300 mg/g
Marker of established
renal disease No Yes

Marker of endothelial Yes Yes
dysfunction

Cardiovascular risk factor Yes Yes

 O U T L I N E
• Introduction
• Epidemiology
• Pathophysiology
• Albuminuria and Clinical Outcomes
• Reducing the Risk Associated with Microalbuminuria
•  Screening
•  Risk Stratification
•  Treatments
• Conclusion

Epidemiology
•  Microalbuminuria is highly prevalent in several disease states Widely
known is the high prevalence in individuals with diabetes
•  A recent worldwide survey showed that in 40% of the patients with
diabetes and without known kidney disease, the levels of urinary
albumin were in the microalbuminuric range
•  Similar data (20%) were found in a large population study (Australian
Diabetes, Obesity, and Lifestyle Study
•  The transition from normo- to microalbuminuria is frequent despite
adequate treatment: 2 to 2.5% per year
•  The prevalence of microalbuminuria in patients with hypertension is
less consistent in large population or cohort studies, varying from 8 to
23%
•  General population studies such as AusDiab and Prevention of Renal
and Vascular End Stage Disease (PREVEND) show an 8 to 11.5%
prevalence of microalbuminuria in individuals with hypertension
•  The Losartan Intervention for Endpoint Reduction (LIFE) trial in
hypertensive patients with electrocardiographic signs of left
ventricular hypertrophy (LVH) showed a 23% prevalence
•  The prevalence of microalbuminuria in the general population is in
the range of 5 to 7% according to several large cohort studies:
PREVEND, Nord-Trøndelag Health Study (HUNT), AusDiab
 Prevalence of albuminuria in the general population
PREVEND

Macro-albuminuria Albumin excretion rates in

>200 mg/l 40,619 citizens
Micro-albuminuria
0.7% of Groningen
20-200 mg/l
7.2%
High-normal
albuminuria
10-20 mg/l
16.6%

Normal
0-10mg/l
75%
Hillege et al; J Int Med 2001;249:519-526
 Microalbuminuria in relation to underlying mechanism
PREVEND in the general population

Diabetes
6.2%
Hypertension
18.9%

“Healthy”
n=2,918
75%

Hillege et al; J Int Med 2001;249:519-526

 O U T L I N E
• Introduction
• Epidemiology
• Pathophysiology
• Albuminuria and Clinical Outcomes
• Reducing the Risk Associated with Microalbuminuria
•  Screening
•  Risk Stratification
•  Treatments
• Conclusion
Proteinuria depends on :
1)  Protein amounts that come to Glomerular
capillary è Serum protein & GFR

2)  Permeability Capillaryè Capilarry wall integrity

& molecular protein pattern (size & Weight,
electrical charge and form)

3)  Tubuli Proximal Reabsorption

Why does microalbuminuria cause
cardio-vascular complications ?
 Microalbuminuria: manifestation of diffuse endothelial cell injury
 O U T L I N E
• Introduction
• Epidemiology
• Pathophysiology
• Albuminuria and Clinical Outcomes
• Reducing the Risk Associated with Microalbuminuria
•  Screening
•  Risk Stratification
•  Treatments
• Conclusion
What are the consequences of
microalbuminuria ?
Does microalbuminuria matter for CV
endpoints and survival ?
The First Study about Albuminuria & CVD Risk
Mortality rate according to urine albumin and proteinuria status

Valmadrid CT et al . Arch Intern Med. 2000; 160

 Albuminuria predicts CV death in the general population
PREVEND

35
29.1

CV death (% per 1000 pj)

30

25

20

15 11.2
10
4.5
5 3.5
0
0 - 14 15 – 29 30 - 300 >300
Albuminuria (mg/day)

Hillege et al; Circulation 2002;106:1777-1782

Same correlation albuminuria and cardiovascular
mortality in type 2 diabetes

Valmadrid, Arch.Int.Med.(2000) 160:1093

 PREVEND
Albuminuria predicts new onset diabetes
in the general population
4.2 year follow-up

14
11.8

New onset Diabetes (%)

12

10
7.9
8

6
4.3
4
2.2
2

0
0 - 14 15 – 29 30 - 300 >300

Brantsma et al; Diabetes Care 2005

Albuminuria (mg/day)
 Albuminuria predicts CKD
PREVEND
in the non-diabetic general population
70

Incidence of Stage 3 CKD (%)

60
58

50

40

30
22
20 13
9
10

0
0 - 14 15 – 29 30 - 300 >300
Albuminuria (mg/day)

Verhave et al; Kidney Int 2004;66(suppl 92):1-4 Stage 3 CKD = creatinine clearance < 60 mL/min
 Urinary albumin excretion (UAE) in diabetics
correlates with retina thickness and transcapillary
albumin escape rate (TER)
retinal thickness

transcapillary escaoe

Knudsen, Diabetes Care (2002) 25:2328

Microalbuminuria and ischemic heart disease
without microalbuminnuria

with microalbuminuria

Borch-Johnsen,Arter.Thromb.Vasc.Biol.(1999)19:1992
Albuminuria - predictor of cardiovascular risk
(Hoorn study)

adjusted rel. risk

smoking 2.8
diabetes type 2 3.7
history CV events 3.6
microalbuminuria 3.3

_ significant risk even when corrected for GFR

Stehouwer and Jager
 Change of albuminuria translates into
change of cardiovascular endpoints (CEP)

high baseline/
high year 1

high baseline/
low year 1

low baseline/
high year 1

low baseline/
low year 1

Ibsen,Hypertension(2005) 45:198

Risk of microalbuminuria - metabolic syndrome

prevalence
CKD (%)
metabolic syndrome
risk factors :
waist > 102 cm/men
fasting glucose>110 mg/dl
HDL-C <40mg/dl/men
triglycerides >140 mg/dl
blood pressure >130/85mmHg

metabolic syndrome risk factors

prevalence
microalbuminuria
(%)

metabolic syndrome risk factors

Chen, Ann.Int.Med. (2004) 140:167

Microalbuminuria correlated to indices of metabolic syndrome

In nondiabetic patients albumin excretion rate

related to :
•  24 h blood pressure
•  Left ventricular mass
•  body weight
•  fasting insulin
•  reduced insulin sensitivity (HOMA)
•  higher creatinine clearance

Del’Omo, Am.J.Kid.Dis. (2002) 40:1

 O U T L I N E
• Introduction
• Epidemiology
• Pathophysiology
• Albuminuria and Clinical Outcomes
• Reducing the Risk Associated with Microalbuminuria
•  Screening
•  Risk Stratification
•  Treatments
• Conclusion
 Screening Methods for Microalbuminuria
DIPSTICK DIRECT MEASUREMENT
(ALB:CREAT RATIO)
Method Colorimetric test Immunoturbidiometric,RIA, high-
performance liquid chromatography
Quantitative No Yes
Units mg/L mg mg albumin/g creatinine
Sample requirement Random urine Random urine
Advantages Office measurement Quantitative, preferred method for
Easy to perform confirmation of microalbuminuria
immediate result More accurate
Disadvantages Not a quantitative test Not immediate
Office staff time
Not definitive (alb:creat ratio required Less accurate
for quantification and confirmation)
Cost per test $4–$6 $10–$20
 Detection & monitoring of microalbuminuria
Albuminuria in Diabetic Kidney Disease
Tong LL, Adler S .Prevention and Treatment of DN In Comprehensive Clinical Nephrology. Ed by RJ. Johnson, 5th edition. Elsevier Saunders 2015
Does treatment of microalbuminuria
matter ?
 Summary of recommendations for patients
with microalbuminuria
q Renoprotection with ACE inhibitors or angiotensin receptor blockers for
patients with diabetes
q  BP control 140/90 mmHg for the general population 130/80 mmHg for
patients with diabetes
q Glycemic control: hemoglobin A1c 7%
q Consider screening in patients with diabetes LDL cholesterol control for
diabetes in the general population 100 mg/dl (2.6 mmol/L) for patients with or
without diabetes 70 mg/dl (1.8 mmol/L) for patients with CVD
q Correct disturbances in triglyceride, HDL, and nonHDL levels
q Smoking cessation
q Dietary limitation of salt (3 g/d) and saturated fat
q Regular exercise and weight control
q Antiplatelet therapy
 Blood pressure and proteinuria lowering effect
of antihypertensives: a meta-analysis

Mean Arterial Pressure (% change)

0 0
Proteinuria (% change)
- 10 -5

- 20 - 10

- 30 - 15

- 40 - 20

- 50 ACEi Others CCB BB Rest - 25

N=34 N=40 N=23 N=8 N=9
N=593 N=632 N=394 N=129 N=109

Gansevoort et al; Nephrol Dial Transplant 1995

 Effects of ACEi
PREVEND IT in the “healthy” with albuminuria

Change from baseline

with Fosinopril
0

Change in - 10
albuminuria
(%) - 20

- 30
- 29.5 *
- 31.43 *
* p < 0.001

3 Months 4 Years

Asselbergs et al; Circulation 2004

 Treatment that lowers albuminuria reduces
PREVEND IT CV risk in the “healthy” with albuminuria

10

Combined CV endpoint (%) 7.5

Placebo Risk
5 Reduction
40%
2.5
ACEi (fosinopril) NNT
29

0
10 20 30 40
0

Months

Asselbergs et al; Circulation 2004

Wolf G,Sharma K.Pathogenesis, Cinical Manifestations & Natural History of DN In Comprehensive Clinical Nephrology. Ed by RJ Johnson,5th ed.Elsevier Saunders 2015
Individualizing Glycemic Goal Setting

Kidney ResClinPract33(2014)121–131
 Goals for Renoprotection & CVD
•  Target blood pressure in non-dialysis CKD:1
o  ACR <30 mg/g: ≤140/90 mm Hg
o  ACR 30-300 mg/g: ≤130/80 mm Hg*
o  ACR >300 mg/g: ≤130/80 mm Hg
o  Individualize targets and agents according to age,
coexistent CVD, and other comorbidities
•  Avoid ACEi and ARB in combination3,4
o  Risk of adverse events (impaired kidney function,
hyperkalemia)

*Reasonable to select a goal of 140/90 mm Hg, especially for moderate albuminuria (ACR 30-300 mg/
g.)2
1)  Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney Int
Suppl. (2012);2:341-342.
2)  KDOQI Commentary on KDIGO Blood Pressure Guidelines. Am J Kidney Dis. 2013;62:201-213.
3)  Kunz R, et al. Ann Intern Med. 2008;148:30-48.
4)  Mann J, et al. ONTARGET study. Lancet. 2008;372:547-553.
 Conclusions
•  Albuminuria indicates the presence of an abnormal urinary excretion
of albumin, signifying endothelial dysfunction and an increased risk for
cardiovascular morbidity and mortality.
•  The association between proteinuria and cardiovascular outcomes has
been demonstrated both in disease population including
hypertensives, diabetic patients, and those with CKD, as well as in
otherwise healthy individuals
•  Reducing albuminuria with pharmacologic therapy has been
associated with improved outcomes in studies employing angiotensin-
converting enzyme inhibitors and angiotensin type-1 receptor
antagonists as part of a therapeutic regimen