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Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults

Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults
Literature review current through: Sep 2023.
This topic last updated: Aug 08, 2022.

INTRODUCTION — Total urinary protein excretion in the normal adult should be less than 150 mg/day. Higher rates of protein excretion that persist beyond a single measurement should be evaluated, as they often imply an increase in glomerular permeability that allows the filtration of normally non-filtered macromolecules, such as albumin.

The assessment of urinary protein excretion and the evaluation of isolated non-nephrotic proteinuria in adults will be reviewed here. The approach to adults with nephrotic-range proteinuria or hematuria and the evaluation of children with proteinuria are presented elsewhere:

(See "Overview of heavy proteinuria and the nephrotic syndrome".)

(See "Etiology and evaluation of hematuria in adults".)

(See "Glomerular disease: Evaluation and differential diagnosis in adults".)

(See "Evaluation of proteinuria in children".)

Issues related to moderately increased albuminuria (formerly called "microalbuminuria"), which is different from non-nephrotic proteinuria, are discussed separately:

(See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus".)

(See "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus".)

(See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

DEFINITIONS

Isolated proteinuria — Isolated proteinuria is defined as proteinuria without abnormalities in the urinary sediment, including hematuria, or a reduction in glomerular filtration rate (GFR), as well as the absence of hypertension or diabetes. In most cases of isolated proteinuria, the patient is asymptomatic, and the presence of proteinuria is discovered incidentally by use of a dipstick during routine urinalysis. The urine sediment is unremarkable (fewer than three erythrocytes per high-power field and no casts), protein excretion is less than 3.5 g/day (non-nephrotic), serologic markers of systemic disease are absent, and there is no hypertension, diabetes, and also no edema or hypoalbuminemia.

This benign presentation of isolated non-nephrotic proteinuria is different from that in patients with more prominent kidney disease who have one or more of the following: nephrotic-range proteinuria (≥3.5 g/day), lipiduria, edema, hypoalbuminemia, and/or an active urine sediment containing red cells (which are often dysmorphic) and red cell casts.

Types of proteinuria — There are four basic types of proteinuria (table 1) [1]:

Glomerular proteinuria

Tubular proteinuria

Overflow proteinuria

Postrenal proteinuria

Glomerular proteinuria (ie, albuminuria) can be identified on a urine dipstick.

Some patients have more than one type of proteinuria. As an example, glomerular diseases, such as focal segmental glomerulosclerosis, can be associated with proximal tubular injury, leading to tubular proteinuria. In addition, patients with multiple myeloma and Bence Jones overflow proteinuria can also develop glomerular proteinuria and increased albumin excretion due to AL (primary) amyloidosis or a monoclonal immunoglobulin deposition disease.

Measuring the urine concentrations of both albumin and total protein (with either two separate tests or with a urine protein electrophoresis) can help determine the type of proteinuria [2]. In this study of 1011 patients, of whom 68 had a kidney biopsy, the ratio of the urine albumin to total protein concentration was generally less than 0.4 in patients with tubular or overflow proteinuria and greater than 0.4 in patients with predominantly glomerular proteinuria.

Glomerular proteinuria – Glomerular proteinuria is due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall. This is a sensitive marker for the presence of glomerular disease. 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 "Glomerular disease: Evaluation and differential diagnosis in adults".)

Tubular proteinuria – Low-molecular-weight proteins, such as beta2-microglobulin, immunoglobulin light chains, retinol-binding protein, and polypeptides derived from the breakdown of albumin, have molecular weights that are generally under 25,000 Daltons in comparison to the 69,000 Daltons 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 is not highly sensitive for the detection of proteins other than albumin and because the quantity of non-albumin proteins excreted is relatively low. 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.

Overflow proteinuria – Increased excretion of low-molecular-weight proteins can occur with marked overproduction of a particular protein, leading to increased glomerular filtration and excretion. This is almost always due to immunoglobulin light chains in multiple myeloma but may also be due to lysozyme (in acute myelomonocytic leukemia), myoglobin (in rhabdomyolysis), or free hemoglobin (in intravascular hemolysis) that is not bound to haptoglobin [6]. In these settings, the filtered load is increased to a level that exceeds the normal proximal reabsorptive capacity. Patients with myeloma kidney also may develop a component of tubular proteinuria since the excreted light chains may be toxic to the tubules, leading to diminished reabsorption. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

Postrenal proteinuria – Inflammation in the urinary tract, which can occur with urinary tract infection, can give rise to increases in urinary protein excretion, although the mechanism is unclear. The excreted proteins are often non-albumin (often IgA or IgG), and only small amounts are excreted. Leukocyturia is frequently present in such patients. Patients with nephrolithiasis or tumors of the urinary tract may also have proteinuria.

Amounts of proteinuria — In normal individuals, low-molecular-weight proteins and small amounts of albumin are filtered by the glomerulus. The actual amount of albumin filtered each day in humans is controversial. The majority view is that no more than approximately 2 to 4 g/day of albumin are filtered normally, but some investigators claim that as much as 200 g of albumin are filtered each day (with nearly all of the filtered albumin "reclaimed" in the early proximal tubule) [7]. Most of the filtered albumin enters the proximal tubule where it is almost completely reabsorbed, either intact or after degradation [8]. The net result is the normal daily protein excretion of less than 150 mg (usually 40 to 80 mg), of which approximately 4 to 7 mg is intact, immunoreactive albumin.

Previously, abnormal proteinuria was generally defined as the excretion of more than 150 mg of total protein per day. However, early kidney disease may be reflected by lesser degrees of proteinuria, particularly increased amounts of albuminuria.

The normal rate of albumin excretion is less than 20 mg/day (15 mcg/min); the rate is approximately 4 to 7 mg/day (3 to 5 mcg/min) in healthy young adults and increases with age and with an increase in body weight. Persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min) is called moderately increased albuminuria (formerly called "microalbuminuria").

Albumin excretion above 300 mg/day (200 mcg/min) is considered overt proteinuria or severely increased albuminuria (formerly called "macroalbuminuria"), the level at which the standard dipstick becomes positive. At this level, much of the protein in the urine consists of albumin. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis" and "Treatment of diabetic kidney disease".)

Even within the normal range, higher amounts of albuminuria are associated with an increased risk of cardiovascular disease. This is discussed elsewhere. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease" and "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease", section on 'High-normal albuminuria'.)

DETECTION AND MEASUREMENT OF TOTAL URINARY PROTEIN EXCRETION — Two semiquantitative methods are available to screen patients for proteinuria. These are the standard urine dipstick and the precipitation of urine proteins with sulfosalicylic acid (SSA). Neither method is quantitative, and, if abnormal proteinuria is suggested by either technique, proteinuria should be quantified using a timed urine collection. (See 'Quantitative measurement' below.)

Semiquantitative measurement

Standard urine dipstick — The standard urine dipstick primarily detects albumin but is relatively insensitive to non-albumin proteins. Thus, a positive dipstick usually reflects glomerular proteinuria. SSA can be used for detection of tubular or overflow proteinuria. (See 'Sulfosalicylic acid test' below.)

The dipstick is very specific but not sensitive to low levels of albumin excretion. The lower limit of detection is a urine albumin concentration of approximately 10 to 20 mg/dL. Thus, patients with moderately increased albuminuria (formerly called "microalbuminuria") will not usually be identified by this method unless the urine is highly concentrated. (See 'Issues with measuring urine albumin' below.)

Dipstick grading (negative to 4+, based upon increasing intensity of color changes) is only semiquantitative and is highly dependent upon urine concentration. Limited data suggest that using the urine-specific gravity to judge urine concentration may improve the ability to identify abnormal proteinuria with the dipstick [9,10]. In one study of more than 2000 patients, for example, a urine dipstick for proteinuria of 2+ or higher was predictive of significant proteinuria (urine protein-to-creatinine ratio (UPCR) greater than or equal to 500 mg/g) regardless of the specific gravity; however, a urine dipstick for proteinuria of trace or 1+ was only predictive of significant proteinuria if the specific gravity was 1.025 or less [9].

False positive urine dipstick results may occur in the following settings:

After the use of iodinated radiocontrast agents [11]. Thus, the urine should not be tested for protein with the standard dipstick for at least 24 hours after a contrast study.

With a highly alkaline urine (pH greater than 8) [12,13].

In the presence of gross hematuria and a urocrit (the percent of urine volume comprised of red blood cells) greater than 1 percent [14].

When specific antiseptics (eg, chlorhexidine, benzalkonium) are used for clean-catch urine samples [15].

Sulfosalicylic acid test — In contrast to the urine dipstick, which primarily detects albumin, SSA detects all proteins in the urine at a sensitivity of 5 to 10 mg/dL [1]. Use of SSA is primarily indicated in patients who present with acute kidney injury, a benign urinalysis, and a negative or trace dipstick, a setting in which myeloma kidney should be excluded. A significantly positive SSA test in conjunction with a negative dipstick usually indicates the presence of non-albumin proteins in the urine, most often immunoglobulin light chains. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

The SSA test is performed by mixing one part urine supernatant (eg, 2.5 mL) with three parts (eg, 7.5 mL) of 3 percent SSA and grading the resultant turbidity according to the following schema (the numbers in parentheses represent the approximate protein concentration) [1]:

0 = no turbidity (0 mg/dL)

Trace = slight turbidity (1 to 10 mg/dL)

1+ = turbidity through which print can be read (15 to 30 mg/dL)

2+ = white cloud without precipitate through which heavy black lines on a white background can be seen (40 to 100 mg/dL)

3+ = white cloud with fine precipitate through which heavy black lines cannot be seen (150 to 350 mg/dL)

4+ = flocculent precipitate (>500 mg/dL)

Similar to the standard urine dipstick, the SSA test will record false positive results in the presence of many of the commonly used iodinated radiocontrast agents [11]. How this occurs is not clear, but protein excretion may be overestimated by as much as 1.5 to 2 g/L. Thus, the urine should not be tested for protein for at least 24 hours after a contrast study. False positive results may also occur in the presence of penicillins, sulfisoxazole, and with gross hematuria [12-14].

Urinary lysozyme — Both the SSA and urine dipstick tests can detect urinary lysozyme, the production and excretion of which may be increased in patients with acute monocytic or myelocytic leukemia. Total lysozyme excretion is usually below 1 g/day but can exceed 4.5 g/day in some patients [16]. Thus, lysozyme excretion should be measured in patients who have a persistently positive urine dipstick for proteinuria in the absence of albuminuria, particularly if other signs of the nephrotic syndrome (such as edema and hyperlipidemia) are absent.

Quantitative measurement — Determination of the degree of protein excretion is a central part of the evaluation of patients with acute and chronic kidney diseases and in patients incidentally noted to have persistent proteinuria by a semiquantitative method. The quantity of protein excretion is clinically important for several reasons:

Most patients with the benign forms of isolated proteinuria excrete less than 1 to 2 g/day.

The degree of proteinuria is prognostically important in patients with primary and secondary glomerular diseases; higher degrees of proteinuria are associated with a more rapid progression to kidney failure, even in the absence of nephrotic syndrome.

The degree of proteinuria is used to monitor the response to therapy, as with immunosuppressive drugs for primary and secondary glomerular diseases or inhibition of the renin-angiotensin system to slow the progression of proteinuric chronic kidney disease. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

24-hour versus spot urine collection — Patients with persistent proteinuria should undergo a quantitative measurement of total protein excretion. The gold standard for measurement of protein excretion is a 24-hour urine collection, with the normal value being less than 150 mg/day.

The major limitations of measuring protein excretion in a 24-hour urine collection include the following:

It is cumbersome for patients.

It is often collected incorrectly. (Over- and under-collections are common.)

The adequacy of the collection can be estimated by quantifying the 24-hour urine creatinine and comparing this value to the expected urine creatinine. As a general rule in adults under the age of 50 years, daily creatinine excretion should be 20 to 25 mg/kg (177 to 221 micromol/kg) of lean body weight in males and 15 to 20 mg/kg (133 to 177 micromol/kg) of lean body weight in females. From the ages of 50 to 90 years, there is a progressive 50 percent decline in creatinine excretion (to approximately 10 mg/kg in males, lower in females) due primarily to a fall in muscle mass. Formulas that incorporate race and weight with or without serum phosphorous in addition to age and sex may improve the estimation of creatinine excretion. This is discussed elsewhere in more detail. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)" and "Assessment of kidney function".)

Due to the limitations of a 24-hour urine collection, a number of shortcuts have been proposed. These shortcuts generally involve measuring the ratio of protein to creatinine (or occasionally the urine albumin-to-creatinine ratio [UACR]) in urine specimens of less than 24 hours' duration. Most commonly, the urine protein-to-creatinine ratio (UPCR) in a spot first- or second-morning urine sample after avoiding exercise is used to estimate 24-hour proteinuria and to follow the effects of treatment in patients with proteinuric kidney diseases. Usually, the urine protein concentration in a spot sample is measured in mg/dL and is divided by the urine creatinine concentration, also measured in mg/dL, yielding a number that estimates the 24-hour protein excretion in grams per day (calculator 1) [17-25]. If SI units are used, the value for the UPCR (or UACR) in units of mg of protein per g of creatinine is divided by 8.8. As an example, a UACR of 30 mg/g creatinine is equivalent to 3.4 mg/mmol creatinine.

The UPCR is easy for patients and providers, and the correlation with daily protein excretion is reasonably good on the population level (figure 1). However, the UPCR may produce errors when applied to the individual patient, especially in those who consistently excrete much more (or less) than 1 g/day of creatinine (which is typical for younger males and many younger females, respectively) or in those who are losing or gaining muscle mass. (See 'Limitations of the UPCR and UACR' below.)

The UPCR and the UACR in spot urine samples are both supported by Kidney Disease: Improving Global Outcomes (KDIGO) as appropriate methods to ascertain kidney damage and aid in the diagnosis of chronic kidney disease. Some devices allow for quantification of urine albumin in spot urine specimens at the point of service (ie, in the clinic rather than the laboratory) [26], although these devices are not widely available. (See "Definition and staging of chronic kidney disease in adults", section on 'Kidney damage'.)

Limitations of the UPCR and UACR — Although the UPCR correlates well with 24-hour urine protein excretion on the population level, its usefulness in predicting the true 24-hour protein excretion in any given individual is debatable (figure 1). There are two major limitations of using random spot urine samples to quantify proteinuria:

The UPCR and UACR are heavily influenced by the urine creatinine concentration (the denominator of the ratio) and therefore by the total daily creatinine production.

Urine protein excretion can vary throughout the day (especially resulting from exercise and posture) and from day to day [27].

Influence of the urine creatinine — The UPCR is useful on the population level because the average 24-hour urine creatinine excretion for the population is assumed to be approximately 1000 mg/day (8.84 mmol/day) per 1.73 m2. Since the denominator of the UPCR is in grams of creatinine (ie, grams of protein per 1 gram of creatinine), the UPCR is an accurate estimate of 24-hour proteinuria only in someone who excretes 1000 mg/day of creatinine. However, the mean population creatinine excretion may actually be substantially higher than 1000 mg/day [28,29]. As an example, in a study of 161 Japanese patients with IgA nephropathy, minimal change disease, or membranous nephropathy, the mean 24-hour urine creatinine content was 1170 mg/day [30].

In addition, the accuracy of the ratio is diminished if creatinine excretion is either markedly higher or lower than the average population value of 1000 mg/day. Specifically:

In individuals with large muscle mass, in whom creatinine excretion may be much higher than 1000 mg/day, the UPCR (or UACR) will underestimate proteinuria.

In a cachectic patient or a patient with small muscle mass, in whom creatinine excretion may be much lower than 1000 mg/day, the UPCR (or UACR) will overestimate proteinuria.

The following studies illustrate how variability in the urine creatinine among individuals can create erroneous estimates of 24-hour proteinuria:

In a study of 16,000 males and females representative of the United States population, urine creatinine concentrations were significantly higher among Black patients and Hispanic American patients than among White patients and significantly higher among males than females [31]. Thus, the UPCR may systematically underestimate 24-hour proteinuria in Black patients, Hispanic patients, and males, while overestimating proteinuria in White patients and females.

In a population-based cohort of 2627 Europeans, the spot UACR systematically underestimated the 24-hour albumin excretion in males (median 4.3 versus 7.4 mg/day) [32]. In addition, lower body weight and older age were associated with higher spot UACR values independent of the true 24-hour albumin excretion.

As a result, the estimated protein (or albumin) excretion rate, which incorporates an estimate of daily creatinine excretion, may be more accurate than the UPCR and UACR. (See 'Estimated albumin excretion rate' below.)

Variability of protein excretion — Urine protein excretion can vary throughout the day [33-37]. Because of this diurnal variation in protein excretion, a random spot UPCR may erroneously estimate 24-hour proteinuria, even if a patient excretes exactly 1000 mg/day of creatinine.

As an example, assume that a patient with lupus has a true 24-hour protein excretion that is stable at 2 g/day. In such patients, protein excretion is approximately 50 percent higher during the middle of the day than it is during sleep [35]. Assume that the patient provides their clinician with a first-morning voided spot urine specimen (which reflects overnight protein excretion [34]) and, one month later, provides a spot urine specimen during a mid-afternoon clinic visit. The UPCR is 1.6 g/g in the first urine specimen and 2.4 g/g in the second. The clinician may interpret these findings to mean that the patient has worsening proteinuria even though there has been no true change.

The extent to which diurnal variability in protein excretion can affect the accuracy of the UPCR was evaluated in a study of 193 patients with lupus nephritis who had both random spot and 24-hour urine collections [36]. The UPCR on the spot urine was compared with the UPCR of the 24-hour urine, rather than the 24-hour protein excretion, in order to account for variations in creatinine excretion. The spot UPCR differed from the 24-hour UPCR by more than 15 percent in 131 patients (68 percent of all patients). In 25 percent of the patients, the spot UPCR differed from the 24-hour UPCR by more than 50 percent.

Accuracy of spot urine estimates — The accuracy of the spot UPCR is important among patients with proteinuric kidney disease. Treatment decisions, such as the initiation or discontinuation of immunosuppressive agents and choice of antihypertensive therapy, are often based upon the degree of proteinuria in a given patient.

On a population level, the 24-hour urine protein excretion and the spot UPCR are reasonably well correlated. However, in individual patients with kidney disease, the spot UPCR often does not accurately predict the result of a 24-hour urine, particularly in patients with lower degrees of protein excretion [36-42]. The following studies illustrate the range of findings:

In a longitudinal study of 302 patients from the Nephrotic Syndrome Study Network (NEPTUNE) cohort, proteinuria was quantified at baseline and at subsequent study visits by same-day spot UPCR and 24-hour urine protein excretion [39]. All patients had biopsy-proven glomerular disease (30, 20, 20, and 30 percent with focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, or other glomerular disease, respectively). Among adults, the spot UPCR accurately identified patients with elevated 24-hour urine protein excretion above clinically significant thresholds (0.5 g, 1.0 g, 2.0 g, 3.0 g, 6.0 g, and 10.0 g). However, the spot UPCR erroneously overestimated 24-hour urine protein excretion in 41 and 28 percent of patients whose excretion was <0.5 g/day and <1.0 g/day, respectively. There was no significant variation in the correlation between 24-hour and spot urine measurements among the different types of glomerular disease.

In a systematic review of 13 studies of patients with lupus nephritis, the correlation coefficient between spot UPCR and 24-hour urine protein excretion ranged from 0.67-1.0 [38]. Despite this moderate-to-high correlation, the accuracy of the spot UPCR was low, particularly among patients with lower levels of protein excretion (ie, <1 g in 24 hours).

Estimated albumin excretion rate — Given the limitations of the UACR resulting from variability in creatinine excretion (see 'Influence of the urine creatinine' above), several investigators have developed an "estimated albumin excretion rate" to more accurately predict the 24-hour albumin excretion [43,44]. The estimated albumin excretion rate (or eAER) can be calculated by multiplying the spot UACR by the expected 24-hour creatinine generation (which can be calculated using a variety of equations) (calculator 2). The eAER was derived in a large study of 1,693 patients with kidney disease using age, sex, race, and the UACR, and then was evaluated in two other large cohorts of patients with chronic kidney disease or diabetes [44]. The eAER was significantly more accurate and less biased than the ACR in predicting the measured 24-hour albumin excretion. Using the eAER rather than the ACR to estimate albumin excretion may be particularly important in patients who have very large or very small muscle mass (eg, young athletic males and older adult females, respectively). Accuracy may be further increased if the eAER is calculated using values from a timed urine collection of 12 hours or more [37].

Similarly, the estimated protein excretion rate (or ePER) can be calculated by multiplying the spot UPCR by the expected 24-hour creatinine generation (calculator 3).

Suggested approach to quantification — The limitations outlined above, however, are not necessarily clinically important in patients with substantial proteinuria, since the exact degree of protein excretion (eg, 3 versus 4 g/day) is less important than the reproducibility of the test and changes with therapy.

We suggest the following approach to measuring and subsequently monitoring protein excretion, which takes into account both the greater accuracy of a complete 24-hour urine collection and the greater ease of monitoring with a spot urine specimen:

A 24-hour urine collection should be obtained during the initial evaluation, measuring the excretion of both protein and creatinine. The completeness of the 24-hour urine collection can be estimated from creatinine excretion, as described above. (See '24-hour versus spot urine collection' above.)

If the initial 24-hour urine collection seems complete, then the rate of protein excretion is probably an accurate estimate. The ePER (or eAER) on this 24-hour specimen can be related to the total amount of proteinuria (or albuminuria) and also compared with a random spot ePER or eAER. Random specimens can subsequently be used to monitor the degree of proteinuria as long as muscle mass appears stable.

If follow-up measurements of the ePER (or eAER) suggest that a clinically important change in protein excretion has occurred, a 24-hour urine collection should be obtained to verify the change in proteinuria before therapy is altered.

Issues with measuring urine albumin — The abnormal excretion of small amounts of albumin in the urine, designated moderately increased albuminuria, may be an early marker of kidney injury in diabetes, hypertension, and glomerular diseases and is a biomarker of cardiovascular disease risk. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

The standard urine dipstick cannot detect moderately increased albuminuria unless the urine is highly concentrated. There are dipsticks especially designed to more reliably detect moderately increased albuminuria [31] that have sensitivities and specificities of 80 to 97 percent and 33 to 80 percent, respectively [45]. However, these dipsticks are not quantitative and suffer from the same issues as standard dipsticks with respect to urine concentration. Thus, moderately increased albuminuria should be quantified in a timed urine specimen, as discussed above.

Direct measurement of albuminuria with traditional immunology-based laboratory methods, such as immunonephelometry, immunoturbidimetry, and radioimmunoassay, can produce results that vary considerably. When the same sample is measured, for example, reported values with one technique may be 1.5- to 3-fold different from that reported with another technique (eg, 10 mg/mL versus 30 mg/mL) [46-48]. These methods may also be associated with significant false negative rates, as some albumin components are not immunologically reactive [49]. Urine albumin measurements should be standardized and reference material and a reference measurement protocol should be put into place for the measurement of albuminuria [50].

By comparison, high-performance liquid chromatography-based measurements are able to assess all intact urinary albumin, even immuno-nonreactive albumin, resulting in increased sensitivity and specificity and higher values for albumin excretion, even in normal individuals [49]. The high-performance liquid chromatography technique may therefore prove useful for earlier and more complete identification of patients with moderately increased albuminuria [51]. Nonetheless, as mentioned above, if the same method is used, the change can be assessed.

APPROACH TO THE PATIENT WITH PROTEINURIA — After a patient has been identified as having proteinuria, a careful medical history and physical examination may reveal a cause, such as diabetes mellitus, malignancy, systemic autoimmune disease, or a prior history of kidney disease. The urine sediment should be examined for indicators of glomerular disease, such as hematuria with dysmorphic red blood cells, specifically acanthocytes; red blood cell casts; and white blood cells or white blood cell casts in the absence of infection. Lipiduria is seen in patients with nephrotic syndrome, which implies glomerular disease. The serum creatinine should be measured and the glomerular filtration rate (GFR) estimated by use of the CKD-EPI formula (calculator 4). (See "Urinalysis in the diagnosis of kidney disease" and "Glomerular disease: Evaluation and differential diagnosis in adults".)

A patient with isolated proteinuria (normal urine sediment, normal kidney function) who has no obvious etiology identified by the history and physical examination should be evaluated for transient proteinuria and orthostatic proteinuria (algorithm 1). If transient proteinuria and orthostatic proteinuria are ruled out, the patient is said to have persistent isolated proteinuria. The subsequent evaluation of patients with persistent isolated proteinuria usually involves referral to a nephrologist and, depending upon the degree of proteinuria and the results of other tests, a kidney biopsy (algorithm 1).

Rule out transient proteinuria — Transient proteinuria is common, especially in young individuals. Transient proteinuria has been reported in 8 to 12 percent of individuals younger than 18 years [52,53] and in approximately 4 percent of college-aged adults [54].

Transient proteinuria is diagnosed if a repeat qualitative test is no longer positive for proteinuria. These patients need no further evaluation and should be reassured that they do not have kidney disease. If proteinuria is present on subsequent examinations and is not associated with orthostatic proteinuria, then persistent isolated proteinuria is diagnosed (algorithm 1).

Transient proteinuria can occur with fever and exercise, perhaps mediated by angiotensin II or norepinephrine-induced alterations in glomerular permeability, as well as with symptomatic urinary tract infection [3,55-57]. When quantified, proteinuria in such patients is generally less than 1 g/day.

With marked exercise, protein excretion can exceed 1.5 mg/min in normal subjects (which is the equivalent of more than 2 g/day if sustained). Exercise is also associated with hematuria and occasionally red blood cell casts, suggesting that the proteinuria is likely glomerular in origin. The excretion of low-molecular-weight proteins in addition to albumin is increased. This suggests both an increase in glomerular permeability (which explains the filtration of albumin) and a reduction in proximal reabsorption (which explains the excretion of normally filtered smaller proteins) [57]. (See "Exercise-induced hematuria".)

Rule out orthostatic proteinuria — Orthostatic proteinuria is characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine. The mechanism by which orthostatic proteinuria occurs is unclear, but neurohumoral activation and altered glomerular hemodynamics may be important. Total protein excretion is generally less than 1 g/day in orthostatic proteinuria but may exceed 3.5 g/day in selected patients [58,59].

Orthostatic proteinuria is a relatively common finding in adolescents (occurring in 2 to 5 percent) but an uncommon disorder in adults over the age of 30 years [55,58,60]. However, one study has suggested that the prevalence may be less (0.65 percent) than previously estimated [61]. It is a benign condition that does not require extensive evaluation (such as a kidney biopsy) or specific therapy [59]. However, kidney function and proteinuria should be followed yearly to monitor for any evidence of progression. In many patients, the condition resolves.

Thus, in patients younger than 30 years who have isolated proteinuria that does not resolve with repeat testing, orthostatic proteinuria should be excluded. This can be done in one of two ways.

The first option involves collection of a split urine sample using the following procedure (table 2):

The first-morning void is discarded.

An upright collection is obtained during the waking hours while the patient is performing normal activities. The patient should finish this collection by voiding just prior to going to sleep.

The patient should then assume the recumbent position and collect nighttime urine (including a void immediately after waking in the morning) into a separate container.

The protein excretion is quantified on the upright collection (which should be abnormal) and the recumbent collection (which should be normal if the patient has orthostatic proteinuria).

A second option avoids the cumbersome 24-hour urine collection:

The patient is provided with a urine specimen cup to bring home.

The patient should empty their bladder just before going to bed, after which they should assume the recumbent position.

Immediately upon waking in the morning, the patient should void into the urine specimen cup, and a urine protein-to-creatinine ratio (UPCR) is calculated.

Since the patient already has had two abnormal urine specimens (to rule out transient proteinuria), a normal UPCR in the first-morning voided urine confirms the diagnosis of orthostatic proteinuria. The drawback to this approach is that the daytime and overnight urine collections are not performed in the same 24-hour period. This drawback can be circumvented by having the patient provide another daytime (upright) urine specimen when they return the first-morning (recumbent) urine specimen to the laboratory for analysis.

It is important to note that many patients with glomerular disease will have a modest reduction in protein excretion when supine. However, the diagnosis of orthostatic proteinuria requires that protein excretion be normal when supine, not merely less than when in the upright position.

Persistent isolated proteinuria — A thorough evaluation is warranted when isolated proteinuria is persistent. Persistent isolated proteinuria usually reflects an underlying kidney or systemic disorder (table 1) [62].

Most patients with persistent proteinuria should have the following tests:

Quantification of urine protein excretion, as described above. (See 'Quantitative measurement' above.)

Measurement of the serum creatinine (with estimation of GFR).

A urine protein immunoelectrophoresis to evaluate for excretion of monoclonal light chains. If urine monoclonal light chains are present, the patient should be evaluated for myeloma. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

A kidney ultrasound examination to rule out structural causes (eg, reflux nephropathy, polycystic kidney disease).

In addition, all patients with persistent proteinuria that is greater than 500 mg/day for total protein (or an estimated protein excretion rate [ePER] greater than 0.5 g/day) or greater than 300 mg/day for albumin (or an estimated albumin excretion rate [eAER] greater than 300 mg/day) should be referred to a nephrologist for decisions regarding further evaluation and management (eg, kidney biopsy, discussed below).

Role of kidney biopsy — A kidney biopsy should generally be done in all patients with proteinuria of more than 3.5 g/day (ie, nephrotic range) or if non-nephrotic proteinuria is associated with an active urine sediment (ie, hematuria or cellular casts) or decreased GFR. However, some patients who are very likely to have nephrotic-range proteinuria due to diabetic nephropathy are not biopsied.

In patients with isolated non-nephrotic proteinuria, a kidney biopsy is usually performed if, with subsequent monitoring, the degree of proteinuria increases and persists above 1 g/day or if the patient develops new glomerular hematuria, hypertension, or a reduction in estimated GFR. In addition, a kidney biopsy may be helpful in patients with isolated non-nephrotic proteinuria to diagnose a suspected systemic process if the diagnosis cannot be made reliably any other way. An overview of the indications for kidney biopsy is provided elsewhere. (See "The kidney biopsy".)

A separate issue is whether a kidney biopsy should be performed in patients with stable isolated non-nephrotic proteinuria, no edema or hypoalbuminemia, and no clinical suspicion or serologies suggestive of a systemic disease that could explain the proteinuria, such as lupus or amyloidosis. In our practice, we evaluate such individuals with an antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), complement component C3 and C4 levels, and hepatitis serologies.

The following issues must be considered:

Management is unlikely to be changed in the short term. As an example, in a prospective study of 25 patients with isolated non-nephrotic proteinuria (≤3.5 g/day) who underwent kidney biopsy, a management decision was changed after kidney biopsy in only 3 patients (12 percent) [63]. The cause of the proteinuria was not provided.

However, some patients with stable isolated non-nephrotic proteinuria eventually develop a reduction in kidney function. As an example, a Japanese study in which 56,000 adults were screened for urinary abnormalities identified 151 patients with asymptomatic proteinuria [64]. At a mean follow-up of 5.8 years, 11 percent developed kidney function impairment (creatinine clearance less than 60 mL/min and/or a serum creatinine greater than 1.5 mg/dL [133 micromol/L]), while the proteinuria disappeared in 23 percent.

The level of persistent isolated non-nephrotic proteinuria that should be evaluated by kidney biopsy has not been well defined. We and most other nephrologists perform a biopsy in patients with non-nephrotic proteinuria of 2 g/day or more but not for proteinuria that is less than 1 g/day [65]. Some would perform a biopsy for persistent proteinuria between 1 and 2 g/day if there are clinical and/or serologic clues suggesting a systemic disease that might be detected by kidney biopsy, such as lupus or primary amyloidosis, or if there is a possible hereditary disease, such as Fabry disease. If such patients are not biopsied, they should be seen at least yearly by a nephrologist to reassess their level of proteinuria and kidney function. At these visits, serologies should be selectively rechecked based upon any new findings on history or physical examination.

PROGNOSIS — Heavy, nephrotic-range proteinuria is associated with poor kidney outcomes in patients with primary and secondary glomerular diseases, and treatments to reduce proteinuria are renoprotective. By contrast, isolated non-nephrotic proteinuria may have a much more indolent course, although a fraction of such patients eventually develop kidney dysfunction. In patients with chronic kidney disease, even low-level proteinuria is associated with poor kidney and general outcomes. In a cohort of mainly White patients with chronic kidney disease and a baseline estimated glomerular filtration rate (eGFR) of 44 mL/min/1.73 m2 and a mean daily urine protein excretion of 0.6 grams, proteinuria measured either by 24-hour urine, urine protein-to-creatinine ratio (UPCR), or urine albumin-to-creatinine ratio (UACR) was a significant risk factor for the composite outcome of death, end-stage kidney disease (ESKD), and >30 percent decline in eGFR [66].

As an example, in a study in which mass screening for asymptomatic proteinuria or asymptomatic hematuria was performed in over 56,000 adults, 151 had isolated proteinuria on dipstick [64]. At a mean follow-up of 5.8 years, proteinuria disappeared in 23 percent, and 11 percent developed kidney function impairment, which was defined as a creatinine clearance less than 60 mL/min and/or a serum creatinine greater than 1.5 mg/dL (133 micromol/L). Proteinuria was less likely to disappear in the 134 individuals with both proteinuria and hematuria (8 percent), and the rate of kidney function impairment was slightly higher (15 percent).

However, patients with higher amounts of isolated non-nephrotic proteinuria may not have an indolent course. In a general population sample of 2574 community dwelling adults, for example, approximately 40 percent of those who had dipstick proteinuria 2+ or greater (corresponding to an albumin concentration of 1 g/L or higher) had a rapid decline in kidney function (defined as an annual decrease in eGFR of 5 percent or more) [67].

Abnormal amounts of proteinuria, even moderately increased albuminuria (formerly called "microalbuminuria"), is an independent and significant risk factor for all-cause mortality, cardiovascular disease, and long-term ESKD risk (figure 2 and figure 3). These data are discussed elsewhere in detail. (See "Chronic kidney disease and coronary heart disease", section on 'Chronic kidney disease as an independent risk factor for CHD' and "Definition and staging of chronic kidney disease in adults".)

LIMITED ROLE OF SCREENING FOR PROTEINURIA — Annual screening for proteinuria is not cost effective in the general population of healthy individuals under age 60 years [62]. By contrast, early detection of proteinuria may be cost effective in high-risk patients (eg, older individuals or those with diabetes or hypertension) [62] since the administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) can slow the progression of proteinuric chronic kidney disease as well as moderately increased albuminuria (formerly called "microalbuminuria") in patients with diabetes. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD' and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Angiotensin inhibition' and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus", section on 'ACE inhibitors and ARBs' and "Treatment of diabetic kidney disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Protein in the urine (proteinuria) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Isolated proteinuria is defined as proteinuria without hematuria or a reduction in glomerular filtration rate (GFR). In most cases of isolated proteinuria, the patient is asymptomatic, and the presence of proteinuria is discovered incidentally by use of a dipstick during routine urinalysis. The urine sediment is unremarkable (fewer than three erythrocytes per high-power field and no casts), protein excretion is less than 3.5 g/day (non-nephrotic), serologic markers of systemic disease are absent, and there is no edema, hypertension, diabetes, or hypoalbuminemia. (See 'Isolated proteinuria' above.)

Types of proteinuria – There are four basic types of proteinuria (table 1) (see 'Types of proteinuria' above):

Glomerular proteinuria

Tubular proteinuria

Overflow proteinuria

Postrenal proteinuria

Amounts of proteinuria – The normal daily protein excretion (including all proteins) is less than 150 mg (usually 40 to 80 mg). The normal rate of albumin excretion is less than 20 mg/day (15 mcg/min); the rate is approximately 4 to 7 mg/day (3 to 5 mcg/min) in healthy young adults and increases with age and with an increase in body weight. Persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min) is called moderately increased albuminuria (formerly called "microalbuminuria"). Persistent albumin excretion above 300 mg/day (200 mcg/min) is considered overt proteinuria or severely increased albuminuria (formerly called "macroalbuminuria"), the level at which the standard dipstick becomes positive. (See 'Amounts of proteinuria' above.)

Detection of proteinuria – Two semiquantitative methods are available to screen patients for proteinuria. These are the standard urine dipstick and the precipitation of urine proteins with sulfosalicylic acid (SSA). Neither method is quantitative, and, if abnormal proteinuria is suggested by either technique, proteinuria should be quantified using a timed urine collection. (See 'Standard urine dipstick' above and 'Sulfosalicylic acid test' above.)

Measurement of protein excretion – Patients with persistent proteinuria should undergo a quantitative measurement of total protein excretion.

The gold standard for measurement of protein excretion is a 24-hour urine collection. The major limitations of measuring protein excretion in a 24-hour urine collection include the following: it is cumbersome for patients, and it is often collected incorrectly (over- and under-collections are common). (See '24-hour versus spot urine collection' above.)

Most commonly, the urine protein-to-creatinine ratio (UPCR) in a spot first- or second-morning urine sample after avoiding exercise is used to estimate 24-hour proteinuria and to follow the effects of treatment in patients with proteinuric kidney diseases. Usually, the urine protein concentration in a spot sample is measured in mg/dL and is divided by the urine creatinine concentration, also measured in mg/dL, yielding a dimensionless number that estimates the 24-hour protein excretion in grams per day (calculator 1). If SI units are used, the value for the UPCR (or urine albumin-to-creatinine ratio [UACR]) is divided by 8.8. (See '24-hour versus spot urine collection' above.)

Although the UPCR correlates well with 24-hour urine protein excretion on the population level, its usefulness in predicting the true 24-hour protein excretion in any given individual is debatable (figure 1). There are two major limitations of using random spot urine samples to quantify proteinuria: the UPCR and UACR are heavily influenced by the urine creatinine concentration (the denominator of the ratio) and therefore by the total daily creatinine production, and urine protein excretion can vary throughout the day. Consequently, the estimated protein excretion rate (ePER) (calculator 3) and estimated albumin excretion rate (eAER) (calculator 2), which can be calculated using information from a spot urine, may be more accurate estimates of daily protein and albumin excretion. (See 'Influence of the urine creatinine' above and 'Variability of protein excretion' above and 'Estimated albumin excretion rate' above.)

Approach to quantifying protein excretion – We suggest the following approach to measuring and subsequently monitoring protein excretion, which takes into account both the greater accuracy of a complete 24-hour urine collection and the greater ease of monitoring with a spot urine specimen (see 'Suggested approach to quantification' above):

A 24-hour urine collection should be obtained during the initial evaluation, measuring the excretion of both protein and creatinine. The completeness of the 24-hour urine collection can be estimated from creatinine excretion, as described above.

If the initial 24-hour urine collection seems complete, then the rate of protein excretion is probably an accurate estimate. The ePER (or eAER) on this 24-hour specimen can be related to the total amount of proteinuria (or albuminuria) and also compared with a random spot ePER or eAER. Random specimens can subsequently be used to monitor the degree of proteinuria as long as muscle mass appears stable.

If follow-up measurements of the ePER (or eAER) suggest that a clinically important change in protein excretion has occurred, a 24-hour urine collection should be obtained to verify the change in proteinuria before therapy is altered.

Approach to the patient with proteinuria – After a patient has been identified as having proteinuria, a careful medical history and physical examination may reveal a cause, such as diabetes mellitus, malignancy, systemic autoimmune disease, or a prior history of kidney disease. The urine sediment should be examined for indicators of glomerular disease, such as hematuria with dysmorphic red blood cells, specifically acanthocytes; red blood cell casts; and white blood cells or white blood cell casts in the absence of infection. Lipiduria is seen in patients with nephrotic syndrome, which implies glomerular disease. The serum creatinine should be measured and the GFR estimated by use of the CKD-EPI formula. (See 'Approach to the patient with proteinuria' above.)

A patient with isolated proteinuria (normal urine sediment, normal kidney function) who has no obvious etiology identified by the history and physical examination should be evaluated for transient proteinuria and orthostatic proteinuria (algorithm 1). (See 'Rule out transient proteinuria' above and 'Rule out orthostatic proteinuria' above.)

If transient proteinuria and orthostatic proteinuria are ruled out, the patient is said to have persistent isolated proteinuria. The subsequent evaluation of patients with persistent isolated proteinuria usually involves referral to a nephrologist and, depending upon the degree of proteinuria and the results of other tests, a kidney biopsy (algorithm 1). (See 'Persistent isolated proteinuria' above and 'Role of kidney biopsy' above.)

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