Proteinuria

Essentials

• Proteinuria is often an incidental finding in chemical screening of urine (dipstick testing) or when determining the albumin/creatinine ratio (ACR) in a single urine sample.
• Transient proteinuria is quite common. Resolution of proteinuria must be confirmed by repeat urine tests.
• In the case of persistent proteinuria an attempt should be made to identify the cause. The most common causes are diabetic kidney disease, hypertensive or atherosclerotic nephrosclerosis and glomerulonephritis.
• If erythrocytes are present in the urine sample in addition to protein or if plasma creatinine concentration is increased, the cause of the renal impairment should always be established, in most cases urgently.
• Diagnostic examinations in specialized care are usually indicated, also in asymptomatic patients, if the daily urinary protein excretion exceeds 1 g (urine ACR 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 investigated Antenatal Clinics and Specialist Care: Consultations, Referrals, Treatment Guidelines

Detection of proteinuria

• 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.
• 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).
• Because of the ease of sampling, the ACR in morning midstream urine should be used as the primary method for quantifying albumin excreted in urine.
  • Increased albuminuria (formerly known as microalbuminuria), is a condition where urinary albumin excretion is permanently increased (urinary ACR 3-30 mg/mmol), despite a negative dipstick test.
  • When urinary ACR exceeds 30 mg/mmol, the condition is referred to as severely increased albuminuria (formerly known as macroalbuminuria) or as proteinuria.

• Urine ACR correlates rather well with protein excretion in a 24-hour urine sample, but the limitations listed below should be considered when interpreting results.
  • Urine ACR measures the amount of albuminuria, whereas protein excretion in a 24-h sample also measures 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. In the diagnosis phase of a kidney disease, it is customary to determine both urine 24-hour protein excretion and ACR once, and if the results correspond, the amount of proteinuria may in future be followed-up by determining ACR.
  • Determination of just the albumin concentration in a single sample is influenced by the amount of urine, complicating interpretation of the result, and hence its use is not recommended.

Transient proteinuria

• Protein may be transiently excreted in urine in association with fever, urinary tract infection, other inflammatory disease, exacerbation of heart failure, macroscopic haematuria or physical exertion, for example.
  • In patients with epidemic nephropathy Epidemic Nephropathy the level of proteinuria may initially be as high as 10 g / 24 h but 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, proteinuria appearing only in the upright position, is usually 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 just before going to bed.
  • Determine urine ACR from the first morning urine sample taken at home after waking up.
  • If the patient has orthostatic proteinuria, the result will be perfectly normal.

Persistent proteinuria

• Suggests some degree of renal damage, and the cause should normally be established. The patient may have no symptoms at all.
• Oedema usually appears when there is nephrotic-range proteinuria (urine 24-hour protein excretion > 3 g / 24 h, urine ACR > 180 mg/mmol). Foamy urine may also occur.
  • The most common causes of nephrotic-range proteinuria are diabetic kidney disease 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.
• Chronic nephropathy can be diagnosed if there is albuminuria (urine ACR > 3 mg/mmol) for more than 3 months.
• Persistent proteinuria can be divided into four main categories according to the pathogenic mechanism: glomerular, tubular, overflow, and postrenal proteinuria.

Workup for persistent proteinuria

• Take the patient history (disease history, medication, symptoms, family history of kidney diseases).
• Examine the patient's clinical status (blood pressure, oedema).
• Quantify the level of proteinuria (if not done yet).
  • The primary method is ACR from morning urine.
  • Timed overnight albumin excretion or 24-hour urinary protein excretion can be used to define the exact amount excreted.
• Check the basic blood count with platelet count, CRP, plasma glucose, electrolytes (potassium, sodium), basic particle count in urine, plasma creatinine (eGFR Gfr Calculator).
• Perform ultrasound scanning of the urinary tract once (to exclude 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, such as haematuria, increased creatinine concentration or hypertension, it will be sufficient to follow up the situation in primary health care.
  • Blood pressure, urine dipstick test, urine ACR, and plasma creatinine every 6 months
  • For patients below the age of 25 years find out whether they have orthostatic proteinuria. Such patients should be followed up annually for a few years (blood pressure, urine dipstick, urine ACR, creatinine).

Treatment and prognostic significance of albuminuria

• Albuminuria predicts an increased risk of death and cardiovascular disease
  • See table Prognosis of CKD by GFR and albuminuria categories:KDIGO 2012, in section 1.3.3 of Summary of recommendation statements, on page 6 in http://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf.
• In chronic renal diseases, the level of proteinuria is associated with the rate at which renal function is deteriorating.
• When albuminuria is diagnosed, the patient's lifestyle and medication should be addressed to reduce albuminuria and thus to slow down the rate of GFR decrease.
  • A low-salt diet, weight loss in patients who are overweight, and quitting smoking reduce albuminuria.
  • 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 or without diabetes Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease.
  • Long-acting GLP-1 analogues (liraglutide, semaglutide and dulaglutide) suppress the worsening of albuminuria in patients with type 2 diabetes Glucagon-Like Peptide Analogues (GLP-1 Analogues) for Type 2 Diabetes and a cardiovascular disease.
  • Steroidal mineralocorticoid receptor blockers (spironolactone, eplerenone) lower blood pressure and reduce proteinuria.
  • The non-steroidal mineralocorticoid receptor blocker finerenone added to an ARB or ACE inhibitor reduces albuminuria and slows down the decrease of GFR levels in patients with type 2 diabetes, chronic kidney disease and albuminuria.
  • For treatment of chronic renal failure, see Treatment of Chronic Renal Failure.
• The level of albuminuria should be followed up regularly.
  • The follow-up frequency depends on the progression rate and severity of the patient's kidney disease.
  • Follow-up is necessary at least once a year.