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Proteinuria

Essentials

Proteinuria is often an incidental finding in chemical screening of urine or when determining albumin/creatinine ratio (ACR) in a single urine sample.
Transient proteinuria is quite common. Resolution of proteinuria must be confirmed by repeated urine tests.
Transient and orthostatic proteinuria can be diagnosed in primary health care.
Unless the proteinuria is transient, the amount of protein excreted in urine should be quantified.
- Because of the ease of sampling, the ACR in morning midstream urine can be used as the primary test method.
- Timed overnight albumin excretion or 24-hour urinary protein excretion can be used to define the exact amount excreted.
If erythrocytes are present in the urine sample in addition to protein, or if renal function is impaired (plasma creatinine levels elevated), the cause of the renal impairment should always be established, in most cases urgently.
Hypertension in association with proteinuria suggests a renal disease.
Diagnostic examinations in specialized care are usually also indicated in asymptomatic patients if the daily urinary protein excretion exceeds 1 g (equivalent to an ACR of 60 mg/mmol), even in the absence of any other abnormal findings.
The cause of nephrotic-range proteinuria (exceeding 3 g/24 h or urine ACR exceeding 180 mg/mmol) should always be sought, and sudden onset nephrotic syndrome Nephrotic Syndrome requires emergency consultation.
If proteinuria is detected in a pregnant woman, the possibility of pre-eclampsia should always be considered Antenatal Clinics and Specialist Care: Consultations, Referrals, Treatment Guidelines

Normal urinary excretion of protein

In the healthy adult, no more than 130 mg protein / 24 h is excreted in the urine. Proteins filtered from plasma, such as albumin and immunoglobulins, as well as proteins from renal or urinary tract cells are excreted in urine.

Transient proteinuria

Protein may be transiently excreted in urine in association with fever, urinary tract infection or physical exertion, for example. The amount excreted is usually below 1 g/24 h. In patients with epidemic nephropathy Nephropathia Epidemica (Ne) the level of proteinuria may initially be as high as 10 g/24 h but it will decrease within a few days. One month after the disease, there should be no more proteinuria.
Resolution of proteinuria should always be confirmed by repeating the urine dipstick test.
- If the twice repeated dipstick test is negative, no further examinations are needed.

Orthostatic proteinuria

Orthostatic proteinuria appearing only in the upright position is a benign phenomenon.
It sometimes occurs in young people but it is quite rare in people over 30 years of age.
Orthostatic proteinuria can be examined as follows:
- Ask the patient to empty his/her bladder in the evening before going to bed. Determine urine ACR from the first morning urine sample. If the patient has orthostatic proteinuria, the result will be normal.
- The diagnosis can be confirmed by taking another midstream urine sample later during the day. A sample taken after the patient has been spending time in the upright position will show albuminuria.
- It should be noted that patients with proteinuria that is associated with a renal disease also excrete less protein in urine during rest than in the daytime. Therefore, the ACR measured in morning urine should be perfectly normal to confirm that the patient has orthostatic proteinuria.

Persistent proteinuria

Suggests some degree of renal damage, and the cause should normally be established. The patient may be totally without symptoms.
If erythrocytes are present in the urine sample in addition to protein, or if renal function is impaired (creatinine level elevated), the cause must always be established, in most cases urgently in specialized care (renal biopsy, specific examinations).
Hypertension found in association with proteinuria usually suggests a renal disease. In such cases, too, referral to specialized care is indicated regardless of the level of proteinuria.
Oedema usually appears when the level of proteinuria exceeds 3 g/24 h (nephrotic-range proteinuria). Foamy urine may also occur.
- The most common causes of nephrotic-range proteinuria are diabetic nephropathy Diabetic Kidney Disease (Diabetic Nephropathy) and glomerulonephritis Glomerulonephrites.
- Hypoalbuminaemia and hypercholesterolaemia concomitantly with nephrotic-range proteinuria is called the nephrotic syndrome Nephrotic Syndrome. This is associated with a thromboembolic tendency.
- The cause of nephrotic-range proteinuria should always be established, and sudden onset nephrotic syndrome requires emergency consultation. The diagnosis is usually made histologically from a kidney biopsy.

Classification of proteinuria

Persistent proteinuria can be divided into four main categories according to the pathogenic mechanism: glomerular, tubular, overflow, and postrenal proteinuria.

Glomerular proteinuria (albuminuria)

Many disorders damaging the glomeruli change the filtering characteristics of the capillary wall. This results in increased glomerular filtration of macromolecules (such as albumin). Albuminuria is a sensitive indicator of glomerular injury.
The level of albuminuria may vary from slight albuminuria to nephrotic-range proteinuria.
The most common causes of glomerular proteinuria (albuminuria)
- Diabetic nephropathy Diabetic Kidney Disease (Diabetic Nephropathy)
- Glomerulonephritis Glomerulonephrites; both primary and secondary
- Amyloidosis
- Nephrosclerosis (associated with hypertension or atherosclerosis)
- Albuminuria (usually below 1 g/24 h) is often detected in patients with metabolic syndrome Metabolic Syndrome or obesity.
- Physical exertion, proteinuria in association with fever, orthostatic proteinuria

Tubular proteinuria

Due to insufficient reabsorption in the proximal tubule of small proteins (e.g. alpha-1-microglobulin and beta-2-microglobulin) that have undergone normal glomerular filtration.
The amount of protein excreted varies from 0.15 to 2 g / 24 h.
The dipstick test cannot detect tubular proteinuria.
The most common causes of tubular proteinuria
- Acute tubulointerstitial nephritis caused by an infection or a drug (e.g. antimicrobial drugs, lithium, NSAIDs, proton pump inhibitors)
- Chronic tubulointerstitial nephritis
- Polycystic kidney disease Renal Cysts
- Secondary phenomenon in association with glomerular diseases

Overflow proteinuria

Overflow proteinuria develops if the plasma concentration of a low molecular weight protein becomes high and glomerular filtration of the protein increases. The tubular ability to reabsorb the protein is exceeded, and protein consequently appears in urine.
The most common reason for this is the secretion of immunoglobulin light chains in association with myeloma Multiple Myeloma (Mm).
The dipstick test cannot detect light chains.

Postrenal proteinuria

Proteinuria is common in association with urinary tract infections Urinary Tract Infections. It may also occur in association with urinary tract tumours Kidney Cancer Bladder Cancer or urolithiasis Urinary Calculi.

Detection of proteinuria

The dipstick test (chemical screening of urine) is a semiquantitative method of measuring urinary protein levels. It measures mainly albumin and does not react to any other proteins in urine, such as immunoglobulin light chains or tubular proteins.
Its sensitivity to albumin is 0.15-0.20 g/l (+). The level of albuminuria can be roughly estimated based on the dipstick test result (table T1).
Moderately increased albuminuria (formerly known as microalbuminuria), is a condition where urinary albumin excretion is permanently increased (urinary ACR 3-30 mg/mmol), although a dipstick test gives a negative result.
When urinary ACR exceeds 30 mg/mmol, the condition is referred to as severely increased albuminuria (formerly known as macroalbuminuria) or as proteinuria.

The reference values for various methods used to diagnose albuminuria

	Single sample, urine albumin/creatinine ratio (ACR, mg/mmol)*	Timed overnight collection, urine albumin (µg/min)	24-hour collection, urine albumin (mg/24 hours)	Chemical screening of urine (albumin)
Normal	<3	<20	<30	-
Moderately increased albuminuria	3-30	20-200	30-300	-
Severely increased albuminuria (proteinuria)	>30	>200	>300	1+ - 2+
Nephrotic-range proteinuria	>180	>1 200	>3 000	3+

* Reference values vary between laboratories. The ranges allow for inaccuracy related to the sample or the assay methods.

Urine ACR correlates rather well with protein excretion in a 24-hour urine sample, but the limitations below should be considered when interpreting results.

Urine ACR measures the amount of albuminuria, whereas protein excretion in a 24-h sample measures also the excretion of other proteins in urine.
Sex and age have an impact on urine ACR. Creatinine excretion in the urine is dependent on the individual's muscle mass, and the excretion diminishes by age. As creatinine excretion decreases, urinary ACR falsely increases.
The sensitivity of urine ACR is good, i.e. a negative result is reliable.
Urine ACR can also be utilized in the follow-up of proteinuria, due to its ease of use. In the diagnosis phase of a kidney disease, it is customary to determine once both urine 24-hour protein excretion and ACR, and if the results correspond to each other, the amount of proteinuria may be followed-up by determining ACR.
Determination of mere albumin concentration in a single sample is influenced by the amount of urine, complicating the interpretation of the result, and hence its use is not recommended.

Finding out the cause of proteinuria

If proteinuria is found in the chemical screening of urine or in determining urine ACR, find out whether there is some evident cause for the finding.
- Urinary tract infection or other inflammatory disease
- Physical exertion preceding the test
- Menstruation
- Macroscopic haematuria
- In-patient treatment for cardiac failure or other severe, acute disease
Repeat the urine test 2-3 times. If proteinuria is no longer found in repeated tests, no further examinations or monitoring are needed.
In patients with persistent proteinuria
- Take the patient history.
- Examine the patient's status (blood pressure, swelling).
- Quantify the level of proteinuria (ACR, timed overnight albumin excretion or 24-hour urinary protein excretion).
- Check the basic blood count with platelet count, CRP, blood glucose, electrolytes, basic particle count in urine, creatinine (eGFR Gfr Calculator).
- Perform ultrasound scanning of the urinary tract once (excluding disorders such as polycystic kidney disease and tumours).
- In addition, consider performing serum protein electrophoresis and testing for free light chains in serum and daily urine protein fractions.
If the level of proteinuria is below 1 g/24 h (urine ACR < 60 mg/mmol) and there are no other abnormal findings, it will be sufficient to follow up the situation.
- Blood pressure, urine dipstick test, urine ACR, and plasma creatinine every 6 months
- Referral to specialized care if the level of proteinuria increases or other findings emerge in addition to proteinuria
For patients below the age of 25 years find out whether they have orthostatic proteinuria. If so, no further examinations are needed.
If, in addition to proteinuria (regardless of its level) haematuria Haematuria, elevated creatinine levels Increased Blood Creatinine Concentration, Egfr and Renal Function Tests or hypertension Secondary Hypertension are also detected, it is usually warranted to find out the cause in specialized care.
If the level of proteinuria exceeds 1 g/24 h (urine ACR > 60 mg/mmol), the reason for proteinuria should be established in specialized care (specific examinations, kidney biopsy) even in the absence of other findings.
If the patient is old or has multiple diseases, it should be considered whether defining the cause will affect treatment.
A specialist can be consulted, as necessary, on the treatment of any diagnosed renal disease (such as diabetic kidney disease).

Effect of albuminuria on prognosis

The appearance of moderately increased albuminuria may be an early sign of a chronic kidney disease if the patient has diabetes Diabetic Kidney Disease (Diabetic Nephropathy).
In type 1 diabetes, screening for albuminuria (ACR) should be done annually when 5 years have passed since the diagnosis, and in type 2 diabetes annually from the diagnosis.
Albuminuria predicts an increased risk of death and cardiovascular disease both in patients with diabetes and in other people.
In chronic renal diseases, the level of proteinuria is associated with the rate at which renal function is deteriorating.
ACE inhibitors and ARBs reduce proteinuria and slow down the impairment of renal function Antiproteinuric and Renoprotective Effects of ACE Inhibitors and Angiotensin II Receptor Blockers.
SGLT2 inhibitors reduce the amount of albuminuria and slow down the decrease of GFR in patients with type 2 diabetes and a cardiovascular disease or several risk factors.
Long-acting GLP-1 analogues (liraglutide, semaglutide and dulaglutide) suppress the worsening of albuminuria in patients with type 2 diabetes and a cardiovascular disease.
When a patient has diagnosed albuminuria, its amount must be followed-up regularly.
- The follow-up frequency depends on the progress rate and severity of the patient's kidney disease.
- Follow-up is necessary at least once a year.

References

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3:1-150 http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf.
National Clinical Guideline Centre. Chronic kidney disease. Clinical Guideline 182.Methods, evidence and recommendations.July 2014http://www.nice.org.uk/guidance/cg182/evidence/full-guideline-pdf-191905165.

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