From: UpToDate
5.
Evaluation of isolated proteinuria in adults
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TYPES OF PROTEINURIA —
There are three basic types of proteinuria — glomerular, tubular, and overflow (show table 1) [2].
Only glomerular proteinuria (ie, albuminuria) is identified on a urine dipstick. Almost all cases of persistent proteinuria are due to glomerular proteinuria.
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Glomerular proteinuria —
Glomerular proteinuria is due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall. The proteinuria associated with diabetic nephropathy and other glomerular diseases, as well as more benign causes such as orthostatic or exercise-induced proteinuria fall into this category. Most patients with benign causes of isolated proteinuria excrete less than 1 to 2 g/day. (See "Differential diagnosis of glomerular disease").
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Tubular proteinuria —
Low molecular weight proteins — such as s2-microglobulin, immunoglobulin light chains, retinol-binding protein, and amino acids — have a molecular weight that is generally under 25,000 in comparison to the 69,000 molecular weight of albumin. These smaller proteins can be filtered across the glomerulus and are then almost completely reabsorbed in the proximal tubule. Interference with proximal tubular reabsorption, due to a variety of tubulointerstitial diseases or even some primary glomerular diseases, can lead to increased excretion of these smaller proteins [3-5].
Tubular proteinuria is often not diagnosed clinically since the dipstick for protein does not detect proteins other than albumin and the quantity excreted is relatively small. The increased excretion of immunoglobulin light chains (or Bence Jones proteins) in tubular proteinuria is mild, polyclonal (both kappa and lambda), and not injurious to the kidney. This is in contrast to the monoclonal and potentially nephrotoxic nature of the light chains in the overflow proteinuria seen in multiple myeloma.
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Standard urine dipstick —
The standard urine dipstick primarily detects albumin via a colorimetric reaction between albumin and tetrabromophenol blue producing different shades of green according to the concentration of albumin in the sample.
The dipstick is insensitive to the presence of non-albumin proteins. Thus a positive dipstick usually reflects glomerular proteinuria. Pure tubular or overflow proteinuria will not be diagnosed unless a 24-hour urine is collected for some other reason, or the urine is tested with sulfosalicylic acid which detects all proteins. (See "Sulfosalicylic acid test" below).
Proteinuria on the urine dipstick is graded from 1+ to 4+, which reflects progressive increases in the urine albumin concentration:
* Negative
* Trace — between 15 and 30 mg/dL
* 1+ — between 30 and 100 mg/dL
* 2+ — between 100 and 300 mg/dL
* 3+ — between 300 and 1000 mg/dL
* 4+ — >1000 mg/dL
The semiquantitative nature of this grading should only be used as a
rough guide to the degree of proteinuria,
since it strongly influenced by the urine volume. A high urine flow rate due to increased water intake or intravenous saline will lower the urine protein concentration by dilution but will not affect total protein excretion.
The urine dipstick is highly specific, but not very sensitive for the detection of mild proteinuria; it becomes positive only when protein excretion exceeds 300 to 500 mg/day. Thus,
the standard urine dipstick is an insensitive methodto detect initial increases in protein excretion above the upper limit of normal of 150 mg/day as occurs in patients with microalbuminuria, which is the earliest clinical manifestation of diabetic nephropathy and, in patients with and without diabetes, is a marker of increased cardiovascular risk. (See "Microalbuminuria" below).
False-positive urine dipstick results are common with many iodinated radiocontrast agents [7]. Thus, the urine should not be tested for protein with the standard dipstick for at least 24 hours after a contrast study.
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Microalbuminuria —
As noted above, the urine dipstick is highly specific, becomes positive only when protein excretion exceeds 300 to 500 mg/day but not very sensitive for the detection of initial increases in protein excretion above the upper limit of normal of 150 mg/day. Thus,
the standard urine dipstick is an insensitive method to detect microalbuminuria, which is the earliest clinical manifestation of diabetic nephropathy and, in patients without diabetes, is a marker of increased cardiovascular risk.
The normal rate of albumin excretion is less than 20 mg/day (15 μg/min); microalbuminuria is defined as persistent albumin excretion between 30 and 300 mg/day (20 to 200 μg/min). Dipsticks are available that detect the urine albumin concentration in this range, but the preferred test for diagnosis and monitoring is the urine albumin-to-creatinine ratio, which is the similar in concept to the urine protein-to-creatinine ratio described in the preceding section.
These issues are discussed in detail elsewhere. (See "Microalbuminuria in type 1 diabetes mellitus" and see "Microalbuminuria in type 2 diabetes mellitus" and see "Microalbuminuria and cardiovascular disease").
SUMMARY
* Urinary protein excretion greater than 150 mg/day that persists beyond a single measurement should be evaluated. Proteinuria may be benign or suggestive of glomerular disease. Heavy proteinuria (>3 g/day), lipiduria, and edema are indicative of glomerular disease.
* There are three types of proteinuria: glomerular, tubular, and overflow proteinuria.
Glomerular proteinuria accounts for virtually all cases of persistent proteinuria and is the only kind that is identified by urine dipstick. (See "Types of proteinuria" above).
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Qualitative tests for proteinuria include urine dipsticks and the sulfosalicylic acid test. These tests provide only
rough estimates of the degree of proteinuria since they are influenced by the urine volume. (See "Measurement of urinary protein" above).
*
The standard urine dipstick detects only albumin and is not sensitive enough to detect microalbuminuria.
Sulfosalicylic acid (SSA) detects all proteins in the urine. (See "Measurement of urinary protein" above)
* Quantitative determination of the degree of proteinuria is provided by a 24-hour urine measurement. Such testing is cumbersome and an alternative, particularly for serial monitoring, is estimation of the total protein-to-creatinine ratio, which correlates with daily protein excretion. (See "Measurement of quantitative protein excretion" above)
* The optimal approach to the patient with proteinuria includes a thorough history, physical examination, and urinalysis. Transient and orthostatic proteinuria should be excluded. Persistent proteinuria warrants a thorough evaluation even when accompanied by a normal urine sediment. The evaluation should include measurement of serum creatinine and an ultrasound examination to rule out structural causes. (See "Approach to the patient with proteinuria" above)
* Patients with persistent proteinuria should be referred to a nephrologist for decisions regarding further management including renal biopsy. A renal biopsy may be performed in the setting of nephrotic syndrome, increasing protein excretion, or an elevation in the plasma creatinine concentration. (See "Approach to the patient with proteinuria" above)
* The renal prognosis of patients with glomerular proteinuria relates to the quantity of protein excreted. Non-nephrotic proteinuria (less than 3 g/day) is associated with a much lower risk of progressive chronic kidney disease than nephrotic range proteinuria. (See "Prognosis" above)
