ملخص

Average daily urinary protein excretion in adults is 80 mg/day, with normal excretion considered to be <150 mg/day. Albumin represents approximately 15% of the daily urinary protein excretion in healthy people, with other plasma proteins (e.g., immunoglobulins, beta-2-microglobulin) and Tamm-Horsfall protein constituting the remaining 85%. Proteinuria varies in amount (from microalbuminuria to nephrotic-range proteinuria) and may be transient or persistent. [1] [2]

Urinary excretion of abnormal quantities of protein for ≥3 months, with or without decreases in glomerular filtration rate (GFR), is diagnostic of chronic kidney disease. [3] The presence of proteinuria is an independent risk factor for death and end-stage renal disease in the general population, as well as in patients with chronic kidney disease. [4] [5] [6] [7] Pharmacological reduction of proteinuria is used as a surrogate marker in the management of chronic kidney disease and many acute glomerular diseases and is associated with improved renal outcomes. [8] [9] [10] [11] [12] [13]

Proteinuria definitions

Microalbuminuria

• Urine albumin: 20-200 mg/g creatinine (men); 30-300 mg/g creatinine (women).

• Associated with increased risk of progressive kidney disease and future cardiovascular events in many populations.

Overt albuminuria

• Urine albumin: >300 mg/day.

Overt proteinuria

• Urine total protein: ≥300 mg/day.

• In many renal diseases, larger amounts of proteinuria are associated with worse renal survival.

Nephrotic range proteinuria

• Urine total protein: ≥3.5 g/day.

• Serum albumin: <3.0 g/dL.

• The presence of nephrotic-range proteinuria with oedema, hypoalbuminaemia, and hyperlipidaemia is defined as nephrotic syndrome.

Glomerular proteinuria

• Urine albumin: 1-20 g/day.

• Passage of protein from glomerular capillary blood (mainly albumin) into the urine.

Tubular proteinuria

• Urine total protein: <2 g/day.

• Passage of low molecular weight proteins (e.g., retinol-binding protein, alpha-2-microglobulin, beta-2-microglobulin) into the urine.

Overflow proteinuria

• Urine total protein: up to 20 g/day.

• Overproduction of small proteins (e.g., myoglobin, light chains) leads to increased glomerular filtration and appearance in the urine.

Epidemiology

Proteinuria is common, and prevalence increases with kidney disease progression. There is evidence to support the prevalence of proteinuria in the US[B Evidence] and that both micro- and overt albuminuria are more common in black people than in white people. As the GFR declines from >90 mL/minute/1.73 m^2 to 15 to 59 mL/minute/1.73 m^2, the prevalence of microalbuminuria increases from 6.0% to 23.2% and overt albuminuria from 0.6% to 8.6%. [14] Prevalence of microalbuminuria has also been shown to increase with increasing body mass index (BMI). Data from a population screening programme in Sheffield, UK, found that the prevalence increased from 3.1% in those with BMI <25% to 27.2% in those with BMI >30. [15]

Detection: qualitative testing

• In the laboratory, proteinuria has traditionally been routinely detected through the use of multi-reagent urinary dipstick testing.

• The presence of urinary albumin is detected by a colorimetric reaction with the dipstick-impregnated reagent.

• Dipstick testing has limited sensitivity for non-albumin protein and is therefore often falsely negative in the presence of predominately tubular or overflow proteinuria.

• The sensitivity of the urinary dipstick for albumin ranges from 83% to 98% with a specificity of 59% to 86%. [16] [17] This reaction depends on the concentration of albumin, such that testing of large-volume, diluted urine underestimates the degree of albuminuria. Similarly, testing highly concentrated urine may overestimate the degree of albuminuria.

• Markedly alkaline pH (>8.0) and administration of iodinated radiocontrast agents can also produce false-positive results.

• Although qualitative dipstick testing is rapid, easy to perform, and commonplace, the false-positive and false-negative rates limit the utility.

Dipstick proteinuria rangesCreated by BMJ Evidence Centre using author content

• Physicians should consult the product-specific information for interpretation of the urine dipstick results with a corresponding urine protein level.

• In the past, sulphosalicylic acid (SSA) was added to urine specimens to precipitate all protein, for the detection of non-albumin proteins. The resultant turbidity is graded on a scale from 0 to 4+. Although SSA testing is still used, semi-quantitative and quantitative testing methods have largely replaced it.

Detection: semi-quantitative testing

• Newer dipsticks have been marketed that can report albumin-to-creatinine ratios in the microalbumin range, as well as total protein-to-creatinine ratios.

• Standardising the protein measurement to the quantity of creatinine in the urine helps to avoid errors introduced by diluted or concentrated urine samples.

• Measuring total protein also allows detection of tubular and overflow proteinuria. The reported sensitivity of these semi-quantitative dipsticks is 80% to 97% with a specificity of 33% to 80%. [18]

Detection: quantitative testing

• The definitive test for detecting proteinuria is the quantitative measurement of urinary protein.

• Twenty-four-hour urine collections have traditionally been used for this purpose, although these collections are prone to over- and under-collection. Moreover, 24-hour urine collections are cumbersome for, and unpopular with, patients. Reporting the total 24-hour urine protein standardised to the 24-hour urine creatinine (g protein/g creatinine) helps to adjust for variations in the duration of collection.

• In women an adequate collection typically has 15 to 20 g of creatinine per kg of body weight, and in men 20 to 25 g/kg.

• Alternatively, the expected grams of excreted creatinine can be estimated by 140 minus age multiplied by weight/5000 [(140 - age) x weight/5000], where weight is in kilograms. This result is multiplied by 0.85 in women. [19]

• More commonly, a urine protein-to-creatinine ratio on a spot urine sample is being used to approximate the 24-hour urine protein excretion.

• A first morning sample most closely estimates 24-hour protein excretion, although a random sample is acceptable if a first morning void is unavailable. [3] [19]

• Because of diurnal variation, it is best to collect spot urine samples at the same time each day if being used to follow up patients long term. Additionally, the correlation of the spot sample with 24-hour excretion is less robust with nephrotic-range proteinuria. The spot ratio may also be less accurate in pregnant women with >300 mg of proteinuria. [20] [21]

• People with body surface areas of 1.73 m^2 excrete roughly 1 g of creatinine. As such, a protein-to-creatinine ratio of 1 g protein/g creatinine in an average-sized person approximates 1 g of proteinuria in 24 hours. It is important to recognise that a ratio of 2.5 g protein/g creatinine in a muscular person who excretes 2 g of creatinine in 24 hours may actually represent nephrotic-range proteinuria of 5 g/day. Similarly, an older, frail woman may excrete <1 g of creatinine per day, and in this setting the spot ratio would overestimate her proteinuria.

• Microalbuminuria is generally measured on a spot urine sample and standardised to urine creatinine.