Dr A. Alfi Dr M.

Al-Ameen
Consultant Nephrologist Nephrology Specialist
Transplant physician Transplant physician
Head of Department of Nephrology KAAH& OC- Jeddah
KAAH& OC, Jeddah
Case
 50 year-old female.  Her medications include:
 Known type 2 diabetes 5 – an over-the-counter
years earlier. multivitamin.
 presented to OPD for – an oral hypoglycemic
routine visit. agent.
 No history of – a statin for known
hypertension. hypercholesterolemia.
 Not known to have had a  She is otherwise well.
previous CV event.  Findings on physical
 She visits the examination are
ophthalmologist annually unremarkable.
with no retionopathy
reported.  Except that her BP that
previously was less than
130/80, became
135/85.
Case: Questions
 Should the woman be screened for microalbuminuria on
this visit ?
 What is the best way to screen for it ?
 If the test result is positive, what does this mean in
terms of the patient's risk for cardiovascular and renal
disease ?
 Is there anything that can be done medically for
microalbuminuria ?
 What follow-up is required, including management of
other risk factors ?
Sheldon et al; 2002CMAJ • September 3, 2002; 167 (5)
Definition of
Microalbuminuria (MA)
 Normally only a small amount of albumin is filtered
at the glomerulus, and most of that albumin is
degraded and reabsorbed by the proximal tubule.

 Usually only <1 mg/dl of albumin appears in the

urine.

 However, a number of conditions can temporarily

or permanently cause an increase in urinary protein
excretion by either altering glomerular membrane
permeability, inducing glomerular capillary
hypertension, or reducing tubular reabsorption.
Tobe et al; Can Med Assoc J 2002;167:499–503.
Definition of
Microalbuminuria (MA)
 Microalbuminuria (MA) is defined as
the range in between: urinary
excretion of albumin of 20 to 200
ug/minute or 30 to 300 mg/24 hours.
Definition of MA

 There is difference between proteinuria and

albuminuria.
 Normal protein in urine should not exceed
150 mg/day.
 This 150 mg protein includes Tamm Horsfall
protein (~70mg), protein of blood group
(~35mg), other proteins (enzymes,
hormones, Ig etc..) and Albumin (0-30mg).
 So, Albumin in urine should not exceed
30mg/day.
Definition of MA

 The standard urinalysis dipstick,

however, can detect albumin only at
levels greater than 300 mg/24 hours,
but MA can be accurately measured by
several widely available sensitive
methods (ELISA, RIA, nephelometry).
Definition of MA

 Normalbuminuria = < 20 ug/minute or

< 30 mg/24 hours.

 Microalbuminuria = the range in

between: urinary excretion of albumin of 20
to 200 ug/minute or 30 to 300 mg/24 hours.

 Macroalbuminuria = more than 200

ug/min, or 300 mg/24 hours.
Definition of MA

Timed Urine
Urine Daily urine
Condition Collection
Dipstick mg /d
mcg/min

Normoalbuminuria Negative < 30 <20

Microalbuminuria Negative 30-299 20-199

Macroalbuminuria Positive >300 >200

Causes of MA

Non-modifiable Modifiable

well proven likely

 Race/ethnicity  Diabetes •High salt diet
 Male gender Hypertension
 • High protein diet
 Older age
 Obesity • Hyperlipidemia
 Low birth weight
 Smoking • Fever
• Exercise
• CHF
• UTI
• Vaginal discharge
Causes of MA

 Langston C in 2004 classified MA as:

1. Prerenal: strenuous exercise, fever, hypothermia,
seizures, and venous congestion.
2. Renal MA: the goal of this lecture
3. Postrenal: UTI and hematuria if there is sufficient
blood to cause the urine to be grossly pink or red.
Langston C;journal of A A H A 40:251-254 (2004)

So, before dignosis of renal MA, prerenal and

postrenal causes shold be excluded
Urine Tests for MA

1. Albumin-to-Creatinine Ratio in a
random spot collection

2. 24-h Urine Collection with

creatinine, allowing the simultaneous
measurement of creatinine clearance

3. Timed (e.g., 4-h or overnight)

collection.
Urine Tests for MA

Albumin-to-Creatinine Ratio is
preferred (easy and accurate):
– First-void or other morning collections are
best because of the known diurnal
variation in albumin excretion

– If this timing cannot be used, uniformity

of timing for different collections in the
same individual should be employed.
Measurement of MA
1. Specific assays:
a. Radioimmunoassay
b. Enzyme-linked immunosorbent assay
c. Nephelometry
2. Reagent tablets or dipsticks for
microalbumin may be carried out, since
they show acceptable sensitivity (95%)
and specificity (93%) when carried out by
trained personnel.
 All positive tests by reagent strips or tablets should
be confirmed by more specific methods.
MA: Susceptible diabetics

 If the urine albumin excretion is in the

upper range of normal (20–30 mg/d).
 If the systolic blood pressure is greater than
130 mm Hg.
 If the glycosylated hemoglobin level is
greater than 8. or
 If the total cholesterol level is greater than
5.24 mmol/L.
Sheldon et al; 2002CMAJ • September 3, 2002; 167 (5)
 MA: PREVALENCES in the
General Population
microalbuminuria macroproteinuria
20-200 mg/l (~7%) >200 mg/l

high-normal
albuminuria
10-20 mg/l
normal 0-10mg/l

Microalbuminuria was present in 7.2% of the subjects and independently

associated with age, gender, hypertension, diabetes, smoking,
previous myocardial infarction and stroke.

Hillege HL et al. J Int Med 2001;249:519-26

Incidence of MA

 Microalbuminuria is likely to be found

in one-third or more of diabetic
patients.
Sheldon et al; 2002 CMAJ • September 3, 2002; 167 (5)
MA: Pathogenesis
Hyperglycemia Functional Changes

Structural Changes Metabolic Changes

Microalbuminuria

Macroalbuminuria

CVD CKD
MA: Pathogenesis
 MA: Pathogenesis
Structural Changes Functional Changes
1) Mesangial Expansion
Metabolic Changes
1) Incresed Renal 1) Advanced glycosylation
2) GBM Thickening
Plasma Flow end products
3) Renal Hypertrophy
4) Glomerulosclerosis 2) Hyperperfusion 2) GF, Cytokines (TGF-B)
3) Afferent Arterioar VD, 3) Protein Kinase C
Efferent Arteriolar VC
4) Polyol pathway
4) Increase
Intraglomerular 5) Reactive Oxygen
Pressure Species
5) Increased Glomerular 6) Endothelial
Hydrostatic Pressure
Dysfunction
6) Hyperfiltration
7) Angiotensin II
8) Glucotoxicity
Pathogenesis:
Role of Endothelial Dysfunction
 MA is thought to be the consequence of generalized
endothelial damage along the vascular tree, including
the glomerulus .

 Enzymes involved in the metabolism of anionic

components of the extracellular matrix (e.g. heparan
sulphate proteoglycan) vulnerable to hyperglycaemia,
seem to constitute the primary cause of albuminuria
and the associated complications.

 Genetic polymorphism of such enzymes is possibly the

main reason for variation in susceptibility.
Deckert et al, Dibetologia, 1989
Natural History in DM 1

 Microalbuminuria is not usually a

presenting finding at the onset of DM1.

 After a 5- to 10-yr duration of diabetes,

susceptible patients develop
intermittent microalbuminuria before
having persistent microalbuminuria
Natural History in DM 1
Natural History in DM 2
 Because of the insidious onset of DM2, the true
duration of the disease is often not known. It has been
reported that a duration of >6 yr of diabetes may have
existed before diagnosis

 Subjects often present with microalbuminuria at that

point.

 However, diabetic nephropathy in DM2 is similar to

nephropathy in DM1 with similar pathology, response
to interventions of glucose control and anti-
angiotensin II therapy, and progression to chronic
renal failure
Significance of MA in
Diabetic Patients
 MA predicts clinical nephropathy.

 MA predicts an increased incidence of

cardiovascular disease and
cardiovascular mortality.

 In other words, MA doubled the risk of

having a cardiovascular event in diabetic
pts.
MA Predicts Overt Nephropathy

 MA is a marker of early stage renal

damage.

 The degree of microalbuminuria is

proportional to the degree of damage.

 Regression of MA decreases the risk.

MA Predicts Overt Nephropathy

 In type 1 Diabetes without specific

intervention:
– Only 80 % of microalbuminuric patients will
develop macroalbuminuria.
– Only 50 % at 10 y and 75% at 20 y of
macroalbuminuric patients willdevelop
ESRD.

American Diabetic Association. Diab Care 2004

MA Predicts Overt Nephropathy

 In type 2 Diabetes without specific

intervention:
– Only 20 – 40 % of microalbuminuric
patients will develop macroalbuminuria.
– Only 20% of macroalbuminuric patients
over 20 y will develop ESRD.

American Diabetic Association. Diab Care 2004

MA and CV Risks

 MA is the strongest independent

determinant of ischaemic heart
disease since confers a two to four-
fold increased risk for this illness
among diabetic and hypertensive or
borderline hypertensive subjects.

Jensen JS et al. Hypertension.2000; 35: 898–903.

All CV Risks Are Related
to MA
 Microalbuminuria is related to a
number of clinical variables such as:
1. Age 6. Hyperinsulinaemia
2. Male gender 7. Hypertension
3. Race 8. Obesity
4. Hyperglycaemia 9. LVH
5. Hyperlipaemia 10. Smoking habits
11. Diet

 Practically, all recognised

cardiovascular risk factors are related
to microalbuminuria.
MA and CV Risks

 Microalbuminuria could simply reflect

an augmented susceptibility to
atherosclerosis linked to common
pathogenetic factors (for instance
endothelial dysfunction).
MA and CV Risks

 The relationship between

microalbuminuria and atherosclerotic
processes seems very tight and
increased urinary albumin excretion
(UAE) has been considered a marker
of prevalent subclinical atherosclerosis.
Jensen JS et al. J Hum Hypertens 1997; 11: 727–732.
Agrawal B et al. J Hypertens 1996; 14: 223– 228.
MA and CV Risks

 In a large cross-sectional study of 11,343

nondiabetic hypertensive patients, those
with microalbuminuria had a significantly
higher prevalence (P < .001) of:
– Coronary artery disease (31% vs 22%)
– Left ventricular hypertrophy (24% vs14%)
– Previous stroke (6% vs 4%)
– Peripheral vascular disease (7% vs 5%).

Agrawal B et al. J Hyperten 1996; 14:223–228.

 MA and CV Risks
Factors that cluster with microalbuminuria
 Insulin resistance
 Central obesity
 Low levels of high-density lipoprotein cholesterol
 High triglyceride levels
 Systolic hypertension
 Lack of nocturnal dip in blood pressure on 24-hour
monitoring
 Salt sensitivity
 Endothelial dysfunction
 Hypercoagulability
 Impaired fibrinolysis
 Renal dysfunction
Is the risk due to later overt
nephropathy?

 HOPE study investigators found

that:
– Microalbuminuria was a strong predictor
of risk for cardiovascular disease even
after adjustment for renal function.
– Thirty eight percent of the HOPE study
patients had diabetes, mostly type 2.
Gerstein et al; Diabetes Care 2000; 23:B35–B39.
Is the risk due to later overt
nephropathy?
 In type 1 diabetes, in contrast to type 2
diabetes, the relation between
microalbuminuria and cardiovascular
morbidity and mortality has been mainly
attributed to the later development of overt
nephropathy.
 However, in adults with type 1 diabetes,
microalbuminuria alone has been associated
with excess cardiovascular mortality.
Agardh CDet al. Diab Res Clin Pract 1997; 35(suppl):113–121.
MA in Essential
Hypertension
 Microalbuminuria can be detected in up to
40% of the population with established
hypertension, particularly in those patients
not controlled satisfactorily by anti-
hypertensive therapy.

 Even blood pressure levels between 130 and

139/80 and 89 mmHg are significantly
associated with microalbuminuria
Ruilope LM. Nephrol Dial Transplant (2004) 19: 524-528
MA and Metabolic Syndrome

 Hyperinsulinaemia and peripheral

resistance to insulin action seem to be
features of microalbuminuric patients

Bigazzi et al; NephrolDial Transplant 1995; 10 [suppl 6]: 10-14

MA and Metabolic Syndrome

 Microalbuminuria is also associated with the

metabolic syndrome, which includes insulin
resistance, low HDL cholesterol levels, high
triglyceride levels, and truncal obesity.

 Current evidence strongly suggests that

hyperinsulinemia is associated with a greater risk
for cardiovascular disease.

 Patients with type 1 and type 2 diabetes mellitus

with microalbuminuria are more insulin-resistant
than those without microalbuminuria.
MA and Metabolic Syndrome

 Insulin promotes albumin transcapillary

excretion, thus determining albuminuria,
but preliminary studies do not seem to
support this conclusion. OR

 MA could be the result of insulin action

at the renal level.
 MA and Metabolic Syndrome
Prevalence of MetS in subjects with microalbuminuria or normoalbuminuria

Palaniappan et al. NHANES III. Am J Hypertens 2003;16:952-8.

MA and Metabolic Syndrome

Microalbuminuria Metabolic Syndrome

CVD Risk Factors CKD Risk Factors

MA and Salt Sensitivity

 Salt-sensitive hypertensive patients show

higher albumin excretion rates than salt-
resistant patients.

 Furthermore, when salt sensitive patients

are given a high-sodium diet they show an
increase in fitration fraction, glomerular
pressure, and albumin excretion rate.

Bigazzi et al; NephrolDial Transplant 1995; 10 [suppl 6]: 10-14

MA and Atherogenic Serum
Lipid Profile

 Microalbuminuria is associated with an increased

LDL:HDL cholesterol ratio and lower HDL cholesterol,
as well as with higher uric acid levels.

 Furthermore, age, BMI, diastolic blood pressure, LDL

cholesterol and uric acid independently and
significantly influence the variation of
microalbuminuria.

 The relationship between these classical atherogenic

risk factors and microalbuminuria suggest that the
latter could be a reflection of atherogenic vascular
damage.
MA & Endothelial
Dysfunction
 Data support the concept that the
presence of MA warning that there is a
problem with the vasculature.
 The presence of MA is a marker of
extensive endothelial dysfunction and
a predictor of increased cardiovascular
risk.

Chugh A, Bakris GL. J Clin Hypertens (Greenwich). 2007 Mar;9(3):196-200.

Recent Report of
Stehouwer and Smulders 2006

 The most likely possibility is that a

common pathophysiologic process, such
as endothelial dysfunction, chronic low-
grade inflammation, or increased
transvascular leakage of
macromolecules, underlies the
association between microalbuminuria
and cardiovascular disease.
Stehouwer CD, Smulders YM.J Am Soc Nephrol. 2006 Aug;17(8):2106-11.
 Albuminuria and CV Risk in
Diabetics Pts
1.0 Status at baseline

Normoalbuminuria
0.9 n = 191

0.8 Microalbuminuria
Survival

n = 86
0.7
Macroalbuminuria
n = 51
0.6
p < 0.01 normoalbuminuria vs. micro- and macroalbuminuria
p < 0.05 microalbuminuria vs. macroalbuminuria
0.5
0 1 2 3 4 5 6
Years
Gall MA. et al. 1995
 MORTALITY with albuminuria

1,00
Fraction of subjects alive

0-10 mg/L Normo albuminuria

10-20 mg/L High Normal
20-200 mg/L Microalbuminuria
0,95

0,90
> 200 mg/L Macroalbuminuria

0,85

0,00
0 200 400 600 800 1000 1200 1400
Days
Hillege HL et al Circulation 2002;106:1777-82
 RISK FACTORS and
ALL CAUSE MORTALITY

Microalbuminuria
Hypertension
Hypercholest.
Smoking
Overweight
Diabetes

Diercks J et al. JACC 2002;40:1401

Mortality rate according to urine
albumin and proteinuria status

Valmadrid et al. Arch Intern Med. 2000; 160:1093-1100.

MA and Age
Urinary Albumin Excretion Increase with Age
13

12 Male
UAE (mg/24h)

11 Female

10

6
20 30 40 50 60 70 80

Age (yrs)
Verhave et al. JASN 2003;14:1330-5
MA and BMI

Urinary Albumin Excretion Increase with  BMI

13

12 Male
UAE (mg/24h)

Female
11

10

6
20 22 24 26 28 30 32
BMI (kg/m2)
Verhave J.C. et al. JASN 2003; 14:1330-5
 MA and SMOKING
Odds ratio (95% CI)
Microalbuminuria
nonsmokers
current smokers
20
>20
former smokers
High normal albuminuria
nonsmokers
current smokers
20
>20
former smokers
0 1 2 3 4

Pinto-Sietsma SJ et al. Ann Int Med 2000;133:585-91

MA and Hormonal Therapy
Premenopausal
Oral contraceptives 1.90 (1.23 - 2.93)
Second generation 2.04 (1.28 - 3.25)
Third generation 1.39 (0.63 - 3.06)

Postmenopausal
Hormone Replacement Therapy 2.05 (1.12 - 3.77)
5 year used 1.28 (0.37 - 4.50)
>5 year used 2.56 (1.32 - 4.97)

MonsterTBM et al. Arch Int Med 2001;161:2000-2005

So…

 Microabuminuria is a sign of early renal

damage
 More importantly, it is an independent
sign of significantly increased risk of MI,
CVA and vascular death.
 Microalbuminuria should be looked for
in all pts with DM and hypertension.
MA: Practical Perspective

 Screening of all diabetic and hypertensive patients by

conventional dipstick for urinary albumin.

 If +ve means that albumin > 300 mg/ 24h  Renal

damage started  evaluate for CKD staging and
management

 If dipstick is –ve  Test for MA (UAE 30-300mg/24h)

 Evaluate for underlying risk factors  immediately
start management strategy.
MA: Practical Perspective

• Determination of MA is recommended in the

initial work-up of subjects with primary hypertension
Verdecchia P, Reboldi G P. Blood Pressure. Volume 13, Number 4/August 2004
MA: Practical Perspective
 MA: Practical Perspective
Primary Secondary
Prevention Prevention
Diabetes
Microalbuminuria D. Nephropathy
Mellitus
• Glycemic Control
• BP Control • BP Control
• ACE-I/ARBs • ACE-I/ARBs
• nd CCB • nd CCB
Tertiary

Preventive Prevention

Strategy
• BP Control
• ACE-I/ARBs
• Anemia Control
• Ca/Po4 Control

ESRD/ Death
Management Strategy

MA
Later
Proteinuria

Glycemia Hypertension Obesity

Lipids Smooking
Management Strategy

Protein
MA
Later

< 1g/d

Strict BG BP
< 125/75 Weight
Control

Normalise Stop
Lipids Smooking
Management Strategy
Later
ACE-I/ARB ACE-I/ARB

Strict BG ACE-I/ARB Control

Control Diet
Normalise Stop
Lipids Smooking
Management Strategy
Management Strategy
 Among available antihypertensive drugs,
angiotensin-converting enzyme (ACE)
inhibitors and the angiotensin II receptor
antagonists seem to be superior to other
antihypertensive drugs in reducing UAE.

 The dual blockade of the renin-angiotensin

system with an ACE inhibitor and an
angiotensin II receptor antagonist is a new
and promising approach to control UAE in
hypertensive patients
Verdecchia P, Reboldi G P. Blood Pressure. Volume 13, Number 4/August 2004
MA: Primary Prevention
Target Diabetic Populations
1. Patients with family history of HTN and/ or
cardiovascular events in 1st degree relatives.
2. Hypertensive patients or even have small
increase in systemic BP, within the normal
range or loss of nocturnal dipping.
Hovind P et al. (2004). Br Med J 328:1105
Daneman D et al (1994) Kidney Int 46:1154–1159

3. Patients with poor glycemic control:

Sustained hyperglycemia HbA1c > 8.6.
4. Patients who have retinopathy.
5. Dyslipidemic patients.
6. Smokers.
MA: Primary Prevention
Target Diabetic Populations
7. Patients with protein intakes greater than
20% of energy intake.
Marion J et al. Current Diabetes Reports 2003, 3:412-417

8. Patients who have slightly elevated urinary

albumin excretion: upper limit of normal.
Rossing P et al. (2002). Diabetes Care 25: 859–864.

9. Patients with short stature or History of Low

Birth weight. Hovind P et al. (2004). Br Med J 328:1105

10. Women using Oral contraceptive.

Ahmed SB et al (2005). Diabetes Care 28:1988–1994.
11. Presence of Cardiovascular risk markers.
MA: 1ry Preventive Measures

1. Glycaemic control should be optimised,

with FBS < 6 mmol/l and/or HbA1c < 7%
2. Mentain Target BP < 130/80
3. ACE-I/ ARBs:
4. Cigarette smoking should be actively
discouraged
5. Mentian Lipid Profile:
a. LDL<100 mg/dl (<2.6 mmol/l)
b. Triglycerides<150 mg/dl (<1.7 mmol/l)
c. HDL>40 mg/dl (>1.0 mmol/l)
MA: 1ry Preventive Measures
MA: 1ry Preventive Measures

6. Protein Intake
– Not to exceed a protein intake of 20% of total energy.
Toeller et al. Diabetologia. 1997 Oct;40(10):1219-26.
– Fish: Diet including a high amount of fish protein lessen the risk of
DN. Mollsten AV et al. Diabetes Care 24:805–810, 2001
– Chicken: A normoproteic diet with chicken as the only source of meat
may represent an alternative strategy for treatment of patients with
type 2 diabetes and microalbuminuria.
Gross JL et al. Diabetes Care, April 1, 2002; 25(4): 645 - 651.
– Fish and Chicken: A normoproteic diet with chicken and fish as the
only meat protein source decreases the GFR in the hyperfiltering
normoalbuminuric IDDM patients. The GFR reduction after this diet is
similar to that observed after an LPD.
Pecis M et al. Diabetes Care 17:665–672, 1994
MA: 1ry Preventive Measures

7. Sodium Intake: High sodium intake should be

avoided.

8. Avoidance of Oral Contraceptive.

9. Correction of CV Risk Factors.
10. Life Style Changes:
 Moderate weight loss (7% body weight)
 Regular physical activity (150 min/week)
 Dietary fiber (14 g fiber/1,000 kcal) and foods
containing whole grains
 Reduced intake of fat to reduce calories.