Proteinuria is associated with cardiovascular and renal disease and is a predictor of end organ damage in patients with hypertension. Detection of an increase in protein excretion is known to have both diagnostic and prognostic value in the initial detection and confirmation of renal disease.[1, 2]
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 dipsticks will show negative with microalbuminuria.
As may occur with multiple myeloma, this may also be undetectable on standard dipstick testing. These are the light chains of immunoglobulins.
This 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.
- Proteinuria is usually albuminuria, but if globulin is lost too, there is serious pathology in the glomeruli.
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.
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.
Causes are manifold and the following table illustrates some of these.
|Causes of Proteinuria|
Primary glomerular causes
Secondary glomerular causes
Other important causes (likely to have multiple pathologies)
Albumin:creatinine (ACR) or protein:creatinine ratio (PCR) is generally more useful than 24-hour collections. A PCR of 100, or ACR of 70, is approximately equal to 1g of urinary protein per 24 hours. Below this level the conversion is non-linear.
- Do not use reagent strips to identify proteinuria unless they are capable of specifically measuring albumin at low concentrations and expressing the result as an ACR.
- To detect and identify proteinuria, use urine ACR in preference to PCR, because it has greater sensitivity than PCR for low levels of proteinuria.
- For quantification and monitoring of high levels of proteinuria (ACR 70 mg/mmol or more), PCR can be used as an alternative.
- ACR is the recommended method for people with diabetes.
- For the initial detection of proteinuria, if the ACR is between 3 mg/mmol and 70 mg/mmol, this should be confirmed by a subsequent early morning sample.
- If the initial ACR is 70 mg/mmol or more, a repeat sample need not be tested.
- Regard a confirmed ACR of 3 mg/mmol or more as clinically important proteinuria.
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.
Proteinuria in excess of 3.5 g per day is likely to lead to a nephrotic syndrome. This usually indicates glomerular disease.
Diseases outside the kidney that can cause proteinuria include:
- Diabetes mellitus
- Connective tissue diseases
- Congestive cardiac failure
Any associated hypertension should be treated aggressively, preferably including an ACE inhibitor or, if there are side-effects, an angiotensin-II receptor antagonist.
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 with PCR >100 mg/mmol or ACR >70 mg/mmol.
- Raised serum creatinine and, if renal function is deteriorating, urgent investigation.
- History suggestive of a systemic disorder such as arthralgia or rash.
- Family history of renal disease.
- If the urinary PCR is >45 mg/mmol with microscopic haematuria, refer to a nephrologist.
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:
- Blood pressure.
- Urine stick testing for protein and blood.
- Serum creatinine.
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.
The possible results of hypoalbuminaemia have been mentioned. Left undetected or untreated, proteinuria may progress to renal impairment or chronic kidney disease.
Patients with proteinuria are also at risk of cardiovascular disease.
Prognosis depends on the underlying cause.
It is estimated that 20% of the patients who develop end-stage kidney disease in the UK have 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 only a small minority of those with positive dipsticks have serious and treatable urinary tract disorders.
Further reading and references
Naderi AS, Reilly RF; Primary care approach to proteinuria. J Am Board Fam Med. 2008 Nov-Dec21(6):569-74. doi: 10.3122/jabfm.2008.06.070080.
Leung AK, Wong AH; Proteinuria in children. Am Fam Physician. 2010 Sep 1582(6):645-51.
Diagnosis and management of chronic kidney disease; Scottish Intercollegiate Guidelines Network - SIGN (June 2008)
Currie G, Delles C; Proteinuria and its relation to cardiovascular disease. Int J Nephrol Renovasc Dis. 2013 Dec 217:13-24. doi: 10.2147/IJNRD.S40522.
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.
Wingo CS, Clapp WL; Proteinuria: potential causes and approach to evaluation. Am J Med Sci. 2000 Sep
Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care; NICE Clinical Guidelines (July 2014)
Proteinuria; The Renal Association
McTaggart SJ; Childhood urinary conditions. Aust Fam Physician. 2005 Nov