PROTEINURIA

-PROTEIN IN URINE

Plasma proteins - essential components of any living being

The kidneys play a major role in the retention of plasma

proteins
glomerular filtration barrier
renal tubules reabsorption of the
passing through glomerular filtration
proteins
Physiology
• Typically large proteins stay in the blood, never enter the renal side of
the glomerulus
• Small proteins can cross, but are usually reabsorbed in the proximal
tubule
The glomerular capillary wall - charge and size-selective properties

high-molecular-weight (HMW) plasma proteins can not enter the urinary space
only a tiny fraction of albumin, globulin, and other large plasma proteins cross
LMW proteins (<20,000 Da) cross capillary wall
they are normally reabsorbed by the proximal tubule
Most healthy individuals

excrete 30 and 130 mg/day of protein

upper limit of normal total urine protein excretion
- 150 to 200 mg/day for adults
the upper limit of normal albumin excretion -
30 mg/day
 Normal tubular protein secretion  a very
small amount of protein that normally
appears in the urine

Tamm-Horsfall protein (uromodulin) HMW

glycoprotein (23 × 106 Da)
formed on the epithelial surface of the thick
ascending limb of the loop of Henle and early distal
convoluted tubule
binds and inactivates the cytokines interleukin-1
and tumor necrosis factor

Immunoglobulin A (IgA)

Urokinase
Normal urine protein excretion
up to 150 mg/d
the detection of abnormal quantities or types
of protein in the urine - an early sign of
significant renal or systemic disease

Normal urine albumin excretion

less than 5 mg/L
low levels of albumin excretion =
microalbuminuria
linked to the identification of the early stages
of diabetic kidney disease

Microalbuminuria
excretion of 30-300 mg/d or 20-200 µg/min
too small to be detected by routine dipstick
screening
Abnormal proteinuria
• Previously, abnormal proteinuria was defined as excretion of protein >
150 mg/day

• Persistent albumin excretion between 30 and 300 mg/day (20 to 200

mcg/min): high albuminuria (formerly called microalbuminuria)

• Albumin excretion > 300 mg/day (200 mcg/min): overt proteinuria or

very high albuminuria (formerly called macroalbuminuria)
MECHANISMS OF PROTEIN HANDLING BY
KIDNEY
• Glomerular capillary
wall permits passage of
small molecules while
restricting
macromolecules
MECHANISMS OF PROTEIN HANDLING
BY KIDNEY

• Normal protein excretion affected by interplay of

glomerular and tubular mechanisms
• Glomerular injury: abnormal losses of intermediate
MW proteins like albumin
• Tubular damage: increased losses of low MW
proteins
Proteinuria-Types
• Glomerular
• Most cases detected
• Larger proteins such as albumen (69,000 molecular weight)
• Tubular
• Usually lower MW proteins (<25,000) not usually detected on dipstick
• Overflow
• I.e.: Myeloma producing large amounts of immunoglobulin
Measurements of proteinuria
• Dipstick tests
• 24 hour urinary protein
• Urine protein/creatinine ratio
• Urine albumin/creatinine ratio
MEASUREMENT OF URINARY PROTEIN

Urine dipstick
Measures albumin concentration via a colorimetric
reaction between albumin and tetrabromophenol blue
producing different shades of green according to the
concentration of albumin in the sample
Negative
Trace — between 15 and 30 mg/dL
1+ — between 30 and 100 mg/dL
2+ — between 100 and 300 mg/dL
3+ — between 300 and 1000 mg/dL
4+ — >1000 mg/dL
Non Persistant Proteinuria
• Fever
• Strenuous exercise
• Cold exposure
• Epinephrine infusion
• Orthostatic
Proteinuria (Quantitative)
Non- nephrotic Nephrotic

• Urine prot/cr: • Urine prot/cr

> 20 mg/mmol > 200 mg/mmol

• 24 h urine collection: • 24 h urine collection:

> 100 mg/m2/day > 1 g/m2/ day
> 4 mg/m2/hr > 40 mg/m2/hr
Urine albumin concentration
• — Although the 24-hour urine collection was the initial gold standard
for the detection of microalbuminuria , it has been suggested that
screening can be more simply achieved by a timed urine collection or
measurement of the urine albumin concentration on an early
morning specimen to minimize changes in urine volume that occur
during the day .
Urine albumin concentration
• One problem with measuring the urine albumin concentration or
estimating it with a sensitive dipstick is that false negative and false
positive results can occur, since the urine albumin concentration is
determined by the urine volume and the amount of albuminuria .
Thus, at a particular rate of albumin excretion, a substantial increase
or decrease in urine volume will respectively lower and raise the urine
albumin concentration. The confounding effect of the urine volume
can be minimized by repeated measurements on early morning
specimens.
Urine albumin-to-creatinine ratio
• — The confounding effect of variations in urine volume on the urine
albumin concentration can be avoided by calculation of the urine
albumin-to-creatinine ratio in an untimed urine specimen.
• A value of 30 to 300 mg/g of creatinine (or, using standard [SI] units,
3.4 to 34 mg/mmol of creatinine) suggests that albumin excretion is
between 30 and 300 mg/day and, therefore, that microalbuminuria is
probably present .
• Values above 300 mg/g (or 34 mg/mmol) are indicative of
macroalbuminuria
Proteinuria (Quantitative)
Non- nephrotic Nephrotic

• Urine prot/cr: • Urine prot/cr

> 20 mg/mmol > 200 mg/mmol

• 24 h urine collection: • 24 h urine collection:

> 100 mg/m2/day > 1 g/m2/ day
> 4 mg/m2/hr > 40 mg/m2/hr
Protein in urine – what next?

• establish persistent proteinuria

• clinical assessment
• interpreting test results
Step 1. Establish persistent proteinuria

proteinuria (1+ or more)

↓
exclude urinary infection
↓
repeat urinalysis after at least one week
↓ ↓
1+ or more continue trace or negative –
no action
Step 2. Initial assessment if persistent proteinuria 1+ or
more

• send early morning urine for albumin/creatinine ratio

• blood tests: U & E’s, fasting glucose, cholesterol and albumin
• Check blood pressure
Step 3: What to do with an albumin/creatinine(mg/mmol)
result
• <5 within reference range
• 5-30 does not indicate renal disease but consider cardiovascular
risk factors
• 31-70 check 6 monthly blood pressure and ACR. No need to refer to
nephrology unless patient also has haematuria, severe
hypertension, eGFR <60 or a systemic disease
• >70 refer to Nephrology
ORTHOSTATIC PROTEINURIA
• Increase in protein excretion in the erect position
compared with levels measured during recumbency
• Proteinuria usually does not exceed 1-1.5 gm/day
• Mechanism postulated to involve an increased
permeability of the glomerular capillary wall and a
decrease in renal plasma flow
• Long-term studies have documented the benign
nature of this condition, with recorded normal renal
function up to 50 years later
Proteinuria - summary

• urine protein testing is worthwhile (vs blood)

• use dipstix to decide when to test further
• albumin : creatinine ratio instead of 24 hour collection.
• use ACR to decide who to refer