Proteinuria

Proteinuria describes the presence of protein in the urine. It is often defined as an amount in excess of 300 mg
per day.
Protein should not normally appear in the urine in detectable quantities.
Microalbuminuria is protein between 30 and 300 mg per 24 hours. This may occur with diabetes and
is discussed in its own article. Standard dip sticks will show negative with microalbuminuria.
Bence-Jones' protein, as may occur with multiple myeloma, may also be undetectable on standard
dipstick testing. These are the light chains of immunoglobulins.
Albuminuria is often taken as synonymous with proteinuria:
Although plasma contains both albumin and globulin, the latter is much less likely to appear
in the urine.
If the filtration system of the glomeruli may be seen as like a sieve or a mesh, then small
holes or tears will permit larger particles than usual to pass through.
These will be the smaller rather than the larger of the particles usually held back, unless
damage is severe.
Hence, under normal conditions, small molecules such as glucose and amino acids will
pass, but not protein.
With mild or moderate damage, smaller proteins such as albumin will pass and only with
severe damage will globulins pass.
Recent work also demonstrates the significance of defective albumin resorption in causing
albuminuria - not purely increased permeability.
[1]
Proteinuria is usually albuminuria, but if globulin is lost too, there is serious pathology in the
glomeruli.
Presentation
Symptoms
Proteinuria is usually asymptomatic, although patients may complain of some "frothiness" of their urine.
Heavy and persistent proteinuria results in hypo-albuminaemia. This may produce ankle swelling, abdominal pain
and breathlessness.
Signs
Patients with asymptomatic proteinuria usually have no signs, but in more severe cases (such as with nephrotic
syndrome) there may be oedema, ascites , hydroceles and pleural effusions as a result of decreased oncotic
pressure. The nephrotic syndrome consists of proteinuria, hypoalbuminaemia and oedema. There may also be
symptoms and signs relating to the underlying cause.
Aetiology
Causes are manifold and the following table illustrates some of these.
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Causes of Proteinuria
[2]
Transient proteinuria
Emotional stress.
Exercise.
Fever.
Urinary tract infection.
Orthostatic (postural) proteinuria*.
Seizures.
Persistent proteinuria.
Primary glomerular causes
Focal segmental glomerulonephritis.
IgAnephropathy (ie Berger's disease).
IgM nephropathy.
Membranoproliferative glomerulonephritis.
Membranous nephropathy.
Minimal change disease.
Secondary glomerular causes
Alport's syndrome.
Amyloidosis.
Sarcoidosis.
Drugs (eg non-steroidal anti-inflammatory drugs (NSAIDs), penicillamine,
gold, angiotensin-converting enzyme (ACE) inhibitors).
Anderson-Fabry disease.
Sickle cell disease.
Malignancies (eg lymphoma, solid tumours).
Infections (eg HIV, syphilis, hepatitis, post-streptococcal infection).
Tubular causes
Aminoaciduria.
Drugs (eg NSAIDs, antibiotics).
Fanconi's syndrome.
Heavy metal ingestion.
Overflow causes
Haemoglobinuria.
Multiple myeloma.
Myoglobinuria.
Other important causes (likely to have multiple pathologies)
Pre-eclampsia/eclampsia.
*Orthostatic proteinuria - protein absent in an early morning sample - uncommon over the age of 30 and
benign.
[2]
Investigations
At least three samples of urine should be checked by stick testing to confirm the persistence of the proteinuria. It
provides a crude estimation of protein concentration as follows:
[3]
Trace = 5-20 mg/dL.
1+ = 30 mg/dL.
2+ = 100 mg/dL.
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3+ = 300 mg/dL.
4+ = greater than 2,000 mg/dL.
Initial investigations should then include the following:
Assess the history with special reference to drug history, family history, past medical history and
occupational history.
Blood pressure must be recorded. Several readings over time may give a more accurate picture.
Blood tests for renal function include U&E and creatinine.
Check for diabetes mellitus with fasting blood glucose.
Check fasting cholesterol, as this is also elevated in nephrotic syndrome.
Check MSU for culture and microscopy. The latter is for casts and microscopic haematuria. Urinary
dipstick testing can be suggestive of a urinary tract infection, but should not be regarded as
diagnostic.
[4]
Measure the urinary ratio of protein to creatinine to give an indication of severity and to extrapolate to
24 hours' loss:
Protein/creatinine ratio >100 mg/mmol - refer to nephrology.
Protein/creatinine ratio >45 mg/mmol with microscopic haematuria - refer to nephrology.
Protein/creatinine ratio at lower levels than above - manage as CKD, according to the
stage.
Proteinuria in excess of 3.5 g per day is likely to lead to a nephrotic syndrome. This usually indicates glomerular
disease.
[2]
Associated diseases
Diseases outside the kidney that can cause proteinuria include:
Diabetes mellitus
Connective tissue diseases
Vasculitis
Amyloidosis
Myeloma
Congestive cardiac failure
Hypertension
Any associated hypertension should be treated aggressively, preferably including an ACE inhibitor or, if there are
side effects, an AT2 receptor blocker.
Referral
The presence of any the following increases the likelihood of significant renal disease, and indicates that further
investigation or referral to a specialist is appropriate:
Proteinuria >1.5 g/day. This is roughly equivalent to a protein concentration of >700 mg/L or
protein/creatinine ratio >40 mg/mmol on single samples.
Haematuria is also present.
Raised serum creatinine and, if renal function is deteriorating, investigation is urgent.
Hypertension.
History suggestive of a systemic disorder such as arthralgia or rash.
Family history of renal disease.
If the urinary ratio of protein/creatinine >45 mg/mmol with microscopic haematuria, refer to a
nephrologist.
[5]
Management
Low-level proteinuria
If proteinuria is <1.5 g protein per day or if it is intermittent, it may be followed up at 6- to 12-monthly intervals with
monitoring of:
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Blood pressure.
Urine stick testing for protein and blood.
Serum creatinine.
Higher-level proteinuria
If proteinuria >1.5 g a day, this is likely to need management by a specialist from the outset and further
investigation may include:
Urine microscopy.
Glomerular filtration rate.
Renal ultrasound.
Possible intravenous urography.
Serological screening for autoantibodies and complement level.
Possibly renal biopsy.
Complications
The possible results of hypoalbuminaemia have been mentioned. Left undetected or untreated, proteinuria may
progress to renal impairment or chronic renal failure.
Patients with proteinuria are also at risk of cardiovascular disease.
Prognosis
Prognosis depends on the underlying cause.
Prevention
It is estimated that 20% of the patients who develop end-stage renal disease in the UK are suffering from
glomerulonephritis. Early recognition and management of proteinuria may result in a delay in the progression to
end-stage disease, or the successful treatment of the underlying disease.
Population screening for proteinuria is not recommended in any healthy, asymptomatic adult population, as four
population-based studies have found that fewer than 1.5% of those with positive dipsticks have serious and
treatable urinary tract disorders.
[6]
Further reading & references
Asymptomatic Proteinuria, Edinburgh Renal Unit
National Kidney Foundation; Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and
Stratification (American)
1. Russo LM, Sandoval RM, McKee M, et al; The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule
cells: Retrieval is disrupted in nephrotic states. Kidney Int. 2007 Jan 17;.
2. Wingo CS, Clapp WL; Proteinuria: potential causes and approach to evaluation.; Am J Med Sci. 2000 Sep;320(3):188-94.
3. Kallen RJ et al, Proteinuria. eMedicine, Apr 2008
4. McTaggart SJ; Childhood urinary conditions.; Aust Fam Physician. 2005 Nov;34(11):937-41.
5. Proteinuria, The Renal Association
6. Woolhandler S, Pels RJ, Bor DH, et al; Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I.
Hematuria and proteinuria.; JAMA. 1989 Sep 1;262(9):1214-9.
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conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its
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For details see our conditions.
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Original Author:
Dr Hayley Willacy
Current Version:
Dr Gurvinder Rull
Last Checked:
18/03/2011
Document ID:
1649 (v22)
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