Prof. dr hab. Anna Wasilewska

“Bubbies appearing on the surface

of the urine indicate renal disease

and a prolonged illness”

Glomerular

Tubular

Overload

Benign

Size of protein

Shape of protein

Charge of protein

Renal hemodynamics

Definitions

Physiology

Physiological proteinuria

Classification of proteinuria

Urine dipstick

Investigation of proteinuria

Proteinuria

› Urine protein excretion > 150mg/day

Microalbuminuria

› Urine [albumin] > 30mg/day but not

detectable by urine dipstick

Nephrotic syndrome

› Urine protein excretion > 3.5g/day (with

hypoalbuminaemia, oedema and

hyperlipidaemia)

Protein filtration through the glomerulus is

dependent on the protein size, shape

and electrical charge

Protein charge

› At physiological pH, most proteins are

negatively charged

› Since the basement membranes are also

negatively charged, most proteins are

retained

Protein size

› Proteins greater than 40kDa are almost

completely retained

› Thus, only small proteins, e.g. retinol-binding

protein, ß2 microglobulin, passes into the

ultrafiltrate

However, most of the filtered proteins are

reabsorbed by the proximal tubules.

Consequently, very little plasma protein

appears in the urine

Normally < 150mg/24hours

In some non-pathological situations, a higher than normal urine protein level is found:

› A concentrated spot urine

› Exercise

› Orthostatic proteinuria

› Contamination e.g. from vagina

Tubular proteinuria

› Tubular dysfunction

› Overflow proteinuria

Glomerular proteinuria

› Selective proteinuria

› Non-selective proteinuria

› microalbuminuria

This occurs when glomerular function is

intact, but protein is lost to the urine

either because of:

› Tubular dysfunction

› Overflow

Tubular dysfunction

› The tubules are damaged and cannot

function properly

› Therefore, the small MW proteins that are

normally filtered are not reabsorbed by the

tubules

› The small MW proteins include: retinol-

binding protein, ß2 microglobulin, lysozyme,

light chains, haemoglobin, myoglobin

Tubular dysfunction

› Pyelonephritis

› Acute tubular necrosis

› Papillary necrosis e.g. analgesic

nephropathy

› Heavy metal poisoning

› SLE

› Fanconi’s syndrome

Overflow proteinuria

› Occurs when the concentration of one of

the small MW proteins is so high that the

filtered load exceeds the tubular

reabsorptive capacity

› Thus, the excess filtered load appears in the

urine

Overflow proteinuria

› Bence Jones proteinuria

› Myoglobinuria

› Haemoglobinuria

When there is glomerular dysfunction,

proteins > 40kDa can escape into the

urine

The most common form of proteinuria

Selective proteinuria

Non-selective proteinuria

Microalbuminuria

Selective proteinuria

› If only intermediate-sized (< 100kDa) proteins

(albumin, transferrin), leaks through the

glomerulus, this is termed selective

proteinuria

Non-selective proteinuria

› When a range of different sized proteins leak

through including larger proteins (IgG), this is

termed non-selective proteinuria

Selectivity

The measurement of the selectivity of

proteinuria used to be popular, however,

this has been replaced by renal biopsy

and electron microscopy

Causes› Glomerulonephritis

› Diabetes mellitus

› Multiple myeloma

› Amyloidosis

› SLE

› Pre-eclampsia

› Penicillamine, gold

Microalbuminuria

› Urine albumin concentrations which are

greater than normal but not detectable by

urine dipstick

Normal urine protein: 150mg/day

About 15-20 mg of the normal urine

protein is albumin

Urine dipsticks detects urine albumin

>300mg/day

Therefore, microalbuminuria is defined

as:

Urine albumin excretion 30-300mg/day

Or

Urine albumin excretion rate 20-

200ug/min.

Microalbuminuria is not detectable by

dipsticks

Therefore, a 24hr or 12 hr urine collection

is required

Clinical significance:

› Correlates with mortality in diabetics and

hypertensives

› Predicts the development of nephropathy in

Type 1 and Type 2 diabetes

Treatment:

› Good BP control, especially by ACE-inhibitors

And

› Good diabetic control

› Postpones the development of diabetic

nephropathy

Shaking

Boiling

Salicylosulphonic acid

Reagent strip

Protein dipstick grading

DesignationApprox. amount

Concentration[6] Daily[7]

Trace 5–20 mg/dL

1+ 30 mg/dL Less than 0.5 g/day

2+ 100 mg/dL 0.5–1 g/day

3+ 300 mg/dL 1–2 g/day

4+ More than 300 mg/dL More than 2 g/day

Commonly used for screening of

proteinuria

Is a plastic strip impregnated with a pH

indicator which changes colour in the

presence of proteins, due to a pH

change

The intensity of the colour correlates with

the concentration of protein in the urine

Mainly detects albumin, and therefore

glomerular proteinuria

Sensitivity: 0.1g/l

False positives:

› When urine is alkaline (some UTI)

› The urine is pigmented (haematuria)

› The urine is concentrated

› Drug / chemical interference (chlorhexidine)

› Contamination with vaginal secretions

› Addition of egg white

False negatives:

› The protein is not albumin

› The urine is dilute

› Incidental finding

› Evidence of renal disease

› Evidence of systemic illness

› Family history of renal disease

› Medications being taken

Renal function

Urine dipstick

› Determine the amount of protein detected

If renal function is normal

and

If protein is trace or 1+

and

There is no significant clinical history

then

Repeat testing

When urine dipstick is repeated, ask the

patient to:

› Refrain from exercise for few hours

› Collect early morning urine to exclude

orthostatic proteinuria

If the findings are negative upon repeat

testing, then the initial positive result may

be due to a transient proteinuria (e.g.

fever, exercise)

Or

A false positive

Further investigation is needed if:

› Still positive upon repeat testing

› Positive clinical history

› Abnormal renal function

› Initial urine protein is > 1+

Underlying disease process

Amount of protein excreted

24 hour urine protein excretion

Creatinine and creatinine clearance

Urine microscopy

Other relevant tests dependent on the

provisional diagnosis

Gives a more accurate assessment of

the severity of the proteinuria

> 150mg/24 hour = proteinuria

> 3.5 g/24 hour (with associated

features) = nephrotic syndrome

For estimation of 24hr urine albumin if

suspect microalbuminuria

And estimation of GFR

Assesses severity of renal dysfunction

To look for casts, white cells and red cells

May be a clue to the diagnosis of

glomerulonephritis, pyelonephritis,

tubular damage

Renal ultrasound if suspect renal disease

Renal biopsy if suspect glomerular disease

Plasma and urine electrophoresis if suspect multiple myeloma with Bence Jones proteinuria

Urine for myoglobin / haemoglobin

HbA1c to assess diabetic control