Summary

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 and may be transient or persistent. [1] [2]

Urinary excretion of abnormal quantities of protein for ≥3 months, with or without a decrease in glomerular filtration rate (GFR), is diagnostic of chronic kidney disease. [3] [4]

Urine albumin measurement is an important component in screening for chronic kidney disease. The presence of proteinuria is an independent risk factor for cardiovascular disease, death, and end-stage renal disease in the general population, and in patients with chronic kidney disease. [5] [6] [7] [8] [9] Presence of proteinuria is associated with a higher mortality in critically ill patients; [10] [11] the degree of proteinuria post renal transplantation is predictive of graft and patient survival. [12]

Reduction of proteinuria by pharmacologic therapy 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. [13] [14] [15] [16] [17] [18] [19]

Proteinuria definitions

Either total urine protein or just the albumin fraction can be measured. Urine albumin measurements are better validated in regard to association with risk for chronic kidney disease progression and cardiovascular events.

Albuminuria

Albuminuria is graded as follows: [20]

  • A1 (normal to mildly increased albuminuria)

    • Albumin excretion rate: <30 mg/24 hours.

    • Albumin-to-creatinine ratio (ACR): <30 mg/g.

  • A2 (moderately increased albuminuria)

    • Albumin excretion rate: 30-300 mg/24 hours.

    • Albumin-to-creatinine ratio (ACR): 30-300 mg/g.

    • Associated with increased risk of progressive kidney disease and cardiovascular events.

  • A3 (severely increased albuminuria)

    • Albumin excretion rate: >300 mg/24 hours.

    • Albumin-to-creatinine ratio (ACR): >300 mg/g.

    • Larger amounts of proteinuria are associated with worse renal survival. These patients should be referred to a nephrologist.

Nephrotic-range proteinuria

  • Urine total protein: ≥3.5 g/day.

  • The presence of nephrotic-range proteinuria with edema, hypoalbuminemia (<3.0 g/dL), and hyperlipidemia is defined as nephrotic syndrome.

Glomerular proteinuria

  • Urine total protein: 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.

Effect of albuminuria on prognosis of chronic kidney disease

Albuminuria is an independent risk factor for the progression of chronic kidney disease. Severely increased levels of albuminuria in the setting of normal GFR may impart a greater risk for progressive chronic kidney disease than mildly reduced GFR with normoalbuminuria.

/best-practice/images/bp/en-us/875-9-iline_default.gifPrognosis of CKD by GFR and albuminuria category: CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global OutcomesReprinted by permission from Macmillan Publishers Ltd: Kidney International Supplements (vol 3, issue 1, January 2013), copyright 2013

In patients with advanced CKD, proteinuria is the strongest predictor of time to end-stage renal disease. [21]

Epidemiology

Proteinuria is common, and prevalence increases with kidney disease progression. There is evidence that both moderately and severely increased albuminuria are more common in black people than in white people. As the GFR declines from >90 mL/minute/1.73 m^2 to 15-59 mL/minute/1.73 m^2, the prevalence of moderately increased albuminuria (ACR <300mg/g) increases from 6.0% to 23.2%, and the prevalence of severely increased albuminuria (ACR >300mg/g) increases from 0.6% to 8.6%. [22]

Detection: qualitative testing

  • In laboratories, proteinuria has traditionally been routinely detected through the use of multireagent 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 nonalbumin 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%. [23] [24] This reaction depends on the concentration of albumin, so the testing of large-volume, dilute 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.

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

/best-practice/images/bp/en-us/875-3-iline_default.gifDipstick proteinuria rangesCreated by BMJ Evidence Centre using author content

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

Detection: semiquantitative 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.

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

  • Measuring total protein also allows detection of tubular and overflow proteinuria. The reported sensitivity of these semiquantitative dipsticks is 80% to 97% with a specificity of 33% to 80%. [25]

Detection: quantitative testing

  • Quantitative testing of albumin using urine albumin concentration or albumin-to-creatinine ratio is sensitive and specific for detecting albuminuria. [26] [27]

  • Measuring urine albumin concentration without measuring urine creatinine concentration is less expensive, and has demonstrated similar sensitivity and specificity as albumin-to-creatinine ratio for screening purposes in diabetics. [27]

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

  • In women, an adequate collection typically has 15 to 20 mg of creatinine per kg of body weight, and in men, 20 to 25 mg/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. [28]

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

  • Albumin to creatinine ratio is more sensitive than protein to creatinine ratio in detecting low levels of proteinuria. [29]

  • 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] [28] [30]

  • 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. [31] [32]

  • 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 recognize 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.

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