Evaluation of proteinuria in adults

INTRODUCTION — 

Total urinary protein excretion in healthy adults 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 evaluation of proteinuria in adults will be reviewed here. Other aspects of proteinuria, including the evaluation of proteinuria in children, are discussed separately.

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

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

●(See "Evaluation of proteinuria in children".)

●(See "Orthostatic (postural) proteinuria".)

●(See "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome".)

Issues related to moderately increased albuminuria (formerly called “microalbuminuria”) 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

Normal and abnormal protein excretion — In healthy individuals, the glomerulus filters low-molecular-weight proteins and small amounts of albumin. Most of the filtered albumin enters the proximal tubule where it is almost completely reabsorbed, either intact or after degradation. The net result is that most healthy adults excrete less than 150 mg/day of protein in the urine [1-3].  

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) [4,5]; it is approximately 4 to 7 mg/day (3 to 5 mcg/min) in healthy young adults and increases with age and 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 (which detects only albumin) becomes positive. At this level, much of the protein in the urine consists of albumin.

Even within the reference range, higher amounts of albuminuria are associated with an increased risk of cardiovascular disease. This is discussed separately. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

Urine total protein excretion that is greater than 3.5 g/day is considered nephrotic-range proteinuria. The nephrotic syndrome is defined as the constellation of nephrotic-range proteinuria, hypoalbuminemia (serum albumin level <3.5 g/dL), and peripheral edema. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

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

●Glomerular proteinuria – Glomerular proteinuria is due to increased filtration of medium- and large-sized proteins (such as albumin) across the glomerular capillary wall due to damage to the glomerular filtration barrier. Glomerular proteinuria (ie, albuminuria) can be identified on a urine dipstick and is a sensitive marker for the presence of glomerular disease. The proteinuria associated with diabetic kidney disease 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.

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. In these settings, the filtered load is increased to a level that exceeds the normal proximal tubular reabsorptive capacity. Patients with light chain cast nephropathy (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", section on 'Mechanisms of injury caused by monoclonal proteins'.)

●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 (usually less than 1 g/day) [6].

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.

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 [7,8] and in approximately 4 percent of college-aged adults [9].

Transient proteinuria is diagnosed if a repeat qualitative test (eg, urinalysis) 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.

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 [10-13]. 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 healthy 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) [12]. (See "Exercise-induced hematuria".)

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 red blood cells [RBCs] per high-power field and no casts), protein excretion is less than 3.5 g/day in a 24-hour collection (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 RBCs (which are often dysmorphic) and RBC casts.

DETECTION AND MEASUREMENT OF PROTEINURIA

Semiquantitative measurement — Two semiquantitative methods are available to screen patients for proteinuria. These are the urine dipstick and the precipitation of urine proteins with sulfosalicylic acid (SSA). If abnormal proteinuria is suggested by either technique, the proteinuria should be quantified. (See 'Quantitative measurement' below.)

Urine dipstick — The urine dipstick primarily detects albumin but is relatively insensitive to non-albumin proteins, most notably immunoglobulin light chains. A positive dipstick usually reflects glomerular proteinuria. SSA can be used for the detection of tubular or overflow proteinuria. (See 'Sulfosalicylic acid test' below.)

The urine dipstick measures albumin concentration via a colorimetric reaction between albumin and tetrabromophenol blue producing different shades of green according to the concentration of albumin in the sample:

●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

Dipstick grading is highly dependent upon urine concentration and may be misleading in certain situations. A dilute urine, for example, will underestimate the degree of albuminuria. By contrast, a concentrated urine may register as 3+ but may not indicate high-grade albuminuria.

False positive urine dipstick results can be caused by a highly alkaline urine (pH >8), highly concentrated urine (specific gravity >1.015), specific antiseptics (eg, chlorhexidine, benzalkonium) used for clean-catch urine samples [14], and use of iodinated radiocontrast agents [15]. Urine should not be tested for protein with the dipstick for at least 24 hours after a contrast study. Of note, glycosuria (as can be seen in patients with diabetes or those taking sodium-glucose cotransporter 2 [SGLT2] inhibitors) can raise the urine specific gravity even when the urine is not highly concentrated. (See "Urinalysis in the diagnosis of kidney disease", section on 'Specific gravity'.)

False negative urine dipstick results can occur with dilute urine (specific gravity <1.010) and when the urine proteins are non-albumin proteins.

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. Use of SSA may be helpful in patients who present with acute kidney injury, a benign urinalysis, and a negative or trace dipstick, a setting in which light chain cast nephropathy (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):

●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 urine dipstick, the SSA test will record false positive results in the presence of many of the commonly used iodinated radiocontrast agents [15]. How this occurs is not clear, but protein excretion may be overestimated by as much as 1.5 to 2 g/dL. 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 [16].

Quantitative measurement — Urine protein excretion can be measured as either total protein or albumin. There are three methods to quantify proteinuria: 24-hour urine collection, spot urine protein-to-creatinine ratio (UPCR), and spot urine albumin-to-creatinine ratio (UACR).

24-hour urine collection — Measurement of daily total protein excretion in a 24-hour urine collection is the traditional, “gold standard” method to quantify proteinuria. Normal total protein excretion is less than 150 mg/day. (See 'Normal and abnormal protein excretion' above.)

The 24-hour collection is started at the usual time the patient awakens. At that time, the first void is discarded and the exact time noted. Subsequently, all urine voids are collected, with the last void timed to finish the collection at exactly the same time the next morning.

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. This is discussed in more detail separately. (See "Assessment of kidney function" and "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)

Urine protein-to-creatinine ratio — Calculation of the UPCR in a random “spot” urine specimen, ideally from a first-morning urine, is the preferred method for estimating urine total protein excretion [17].

The urine protein concentration in a spot sample (measured in mg/dL) is divided by the urine creatinine concentration (also measured in mg/dL), yielding a number (with the units mg protein/mg creatinine or g protein/g creatinine) that estimates the 24-hour protein excretion in grams per day (calculator 1) [18-21]. Some laboratories may report the UPCR in mg protein/g creatinine; if so, the ratio will estimate the 24-hour protein excretion in mg per day.

In adults, the normal value for the UPCR is <0.2 mg/mg (<200 mg/g or <23 mg/mmol). A UPCR of 1.5 mg/mg (1500 mg/g or 170 mg/mmol) suggests that protein excretion is 1.5 g/day.

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, in individual patients with kidney disease, the spot UPCR may be less accurate in those with lower degrees of protein excretion (ie, <1 g in 24 hours) [22-28].

There are two major limitations of using random spot urine samples to quantify proteinuria:

●Influence of the urine creatinine – The UPCR is heavily influenced by the urine creatinine concentration (the denominator in the ratio) and therefore by the daily total creatinine production. At the population level, the UPCR is useful 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, g of protein per 1 g 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 be substantially higher than 1000 mg/day [29,30].

In addition, the accuracy of the UPCR 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 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 will overestimate proteinuria.

Urine creatinine can also be impacted by other factors, such as sex and race [31,32]. As an example, in a study of 16,000 males and females representative of the United States population, urine creatinine concentrations were higher among Black patients and Hispanic American patients than among White patients and 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.

Marked glycosuria (as can be seen in patients with diabetes or those taking SGLT2 inhibitors) and ketonuria may increase urine creatinine levels when measured by the Jaffe creatinine assay and falsely lower the UPCR [33,34].

As a result, the estimated protein excretion rate (PER), which incorporates an estimate of daily creatinine excretion, may be more accurate than the UPCR (calculator 2). However, the urine PER is not commonly used in clinical practice.

●Variability of protein excretion – Urine protein excretion can vary throughout the day (especially resulting from exercise and posture) [22,23,35,36] and from day to day [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 systemic lupus erythematosus (SLE) 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 [36]. Assume that the patient provides their clinician with a first-morning voided spot urine specimen (which reflects overnight protein excretion [35]) 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 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.

Urine albumin-to-creatinine ratio — Calculation of the UACR in a random “spot” urine specimen, ideally from a first-morning urine, is the preferred method for estimating albumin excretion [17]. The UACR is also the preferred method for screening for albuminuria among all patients with diabetes. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Detection recommendation'.)

The urine albumin concentration in a spot sample (measured in mg/dL) is divided by the urine creatinine concentration (also measured in mg/dL) and then multiplied by 1000, yielding a number (with the units of mg albumin per g creatinine) that estimates the 24-hour albumin excretion in mg per day (calculator 3).

In adults, the normal value for the UACR is <30 mg/g (<3.4 mg/mmol). A UACR of 30 to 300 mg/g (3.4 to 34 mg/mmol) suggests that albumin excretion is between 30 and 300 mg/day and, therefore, that moderately increased albuminuria (formerly called “microalbuminuria”) is probably present. Values above 300 mg/g (34 mg/mmol) are indicative of severely increased albuminuria (formerly called "macroalbuminuria"). (See 'Normal and abnormal protein excretion' above.)

Like the UPCR, the UACR is also influenced by the urine creatinine concentration (the denominator in the ratio) and can be affected by diurnal variation in albumin excretion. These limitations are discussed above. Calculating the urine albumin excretion rate (AER) (calculator 4), which incorporates an estimate of daily creatinine excretion, may be more accurate but is not commonly performed in clinical practice. (See 'Urine protein-to-creatinine ratio' above.)

APPROACH TO THE ADULT WITH PROTEINURIA

Initial evaluation — The initial evaluation of patients with a positive urine dipstick for protein includes a targeted history, physical examination, and laboratory testing to identify potential causes and to determine whether further evaluation and referral to a specialist (nephrology) are warranted.

History — We perform a targeted history to identify potential causes and risk factors for proteinuria, with a focus on the following elements:

●Associated symptoms – We assess for the presence of associated symptoms, such as:

•Foamy urine (ie, appearance and persistence of multiple layers of small to medium bubbles in urine voided into a container), which can be seen with excess protein in the urine [38]. The timing of the onset of foamy urine may be helpful in determining the onset of proteinuria. However, not all patients with proteinuria will experience foamy urine. A single layer of large bubbles in the urine that quickly dissipates is considered normal.

•New-onset or worsening swelling in the upper or lower extremities, abdomen, or face.

•Visible (gross) blood in the urine. Blood in the urine may appear red, pink, “rusty”, or brown in color. (See "Evaluation of hematuria in adults", section on 'Definitions'.)

•Dysuria with or without fever, which may indicate a urinary tract infection.

•Systemic symptoms, such as fever, rash, joint pain, or weight loss, which might suggest a systemic condition associated with glomerular disease (eg, systemic lupus erythematosus [SLE]).

●Causes of transient proteinuria – We ask about recent events that can be associated with transient proteinuria, such as fever, vigorous exercise, or current urinary tract infection. (See 'Transient proteinuria' above.)

●Comorbid health conditions – We assess the patient for other comorbid health conditions that can be associated with proteinuria, such as:

•A history of hypertension or diabetes mellitus. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Albuminuria and decreased glomerular filtration rate'.)

•A history of autoimmune disease, such as SLE, or systemic vasculitis (eg, granulomatosis with polyangiitis or microscopic polyangiitis, mixed cryoglobulinemia). (See "Lupus nephritis: Diagnosis and classification", section on 'Clinical features' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Kidney involvement' and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Kidney involvement'.)

•A history of malignancy. (See "Overview of kidney disease in patients with cancer", section on 'Proteinuria or nephrotic syndrome in patients with cancer'.)

•A history of hepatitis B (HBV), hepatitis C (HCV), or HIV infection. (See "Kidney disease associated with hepatitis B virus infection" and "Overview of kidney disease associated with hepatitis C virus infection" and "Kidney disease in patients with HIV".)

•Prior history of kidney disease.

●Medications – We review the patient’s medications for agents that may cause proteinuria, including the following:

•Nonsteroidal antiinflammatory drugs (NSAIDs), which can cause acute or chronic interstitial nephritis as well as minimal change disease and membranous nephropathy. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Drugs' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.)

•Anticancer therapies, specifically vascular endothelial growth factor (VEGF) inhibitors (eg, bevacizumab, small molecule antiangiogenic tyrosine kinase inhibitors [TKIs]) and immune checkpoint inhibitors (eg, pembrolizumab, ipilimumab). (See "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'Class effects of antiangiogenic agents'.)

•Bisphosphonates (particularly pamidronate), which have been associated with collapsing focal segmental glomerulosclerosis (FSGS). (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Bisphosphonates and other drugs'.)

•Alpha lipoic acid, which has been associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.)

•Hydralazine, which has been associated with drug-induced antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Hydralazine'.)

●Family history – We assess for any family history of kidney disease.

Physical examination — Physical examination should be guided by the clinical history and may include the following assessments:

●Blood pressure measurement – New or worsening hypertension may be seen in patients with glomerular disease and other underlying kidney disease.

●Assessment for edema – New or worsening edema and recent weight gain could suggest underlying glomerular disease.

●Skin examination – The skin should be examined for new rashes or purpura that could suggest a systemic condition associated with glomerular disease (eg, SLE).

Laboratory testing — We obtain the following laboratory tests as part of the initial evaluation:

●Urinalysis and microscopic examination of the sediment – A urinalysis should be performed to confirm persistent proteinuria, evaluate for signs of urinary tract infection, and check for the presence of hematuria. If there are signs of urinary tract infection (eg, white blood cells [WBCs] in the urine, positive dipstick for leukocyte esterase and/or nitrite), we obtain a urine culture to confirm infection.

The urine sediment should be examined by microscopy for indicators of glomerular disease, such as dysmorphic red blood cells (RBCs), specifically acanthocytes; RBC casts; and WBC casts in the absence of infection. Urine microscopy should be performed by an experienced examiner (eg, a nephrologist). If an experienced examiner is not available, referral to a nephrologist is reasonable. (See "Urinalysis in the diagnosis of kidney disease".)

●Spot urine test for quantification of proteinuria – In all patients with a positive urine dipstick for protein, we quantify the proteinuria, either with a spot urine protein-to-creatinine ratio (UPCR) or a urine albumin-to-creatinine ratio (UACR). For most patients without diabetes, we prefer the UPCR since this ratio provides an estimate of total urine protein excretion (albumin and non-albumin proteins). For patients with diabetes, the UACR is the preferred test to quantify albuminuria. (See 'Urine protein-to-creatinine ratio' above and 'Urine albumin-to-creatinine ratio' above.)

●Basic metabolic panel – A basic metabolic panel should be obtained to assess kidney function (serum creatinine and estimated glomerular filtration rate [eGFR]).

Subsequent approach based on initial evaluation — Subsequent evaluation of the patient is guided by the clinical presentation and the findings of the initial evaluation. (See 'Initial evaluation' above.)

Patients with associated symptoms, an abnormal urinalysis, or kidney function impairment — In patients who have any associated signs and symptoms concerning for glomerular disease (eg, foamy urine, edema, gross [visible] hematuria, systemic symptoms), urine findings suggestive of glomerular disease (eg, dysmorphic RBCs, specifically acanthocytes; RBC casts; and WBCs or WBC casts in the absence of infection), or evidence of kidney function impairment (elevated serum creatinine or reduced eGFR), we refer to nephrology for further evaluation and management. Such evaluation may involve additional laboratory testing and often a kidney biopsy to obtain a more definitive diagnosis. (See "Glomerular disease: Evaluation and differential diagnosis in adults" and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Diagnosis and evaluation'.)

All other patients — In patients who have no associated symptoms, no urine findings suggestive of glomerular disease, and normal kidney function, we take the following approach:

●No abnormal proteinuria – If quantification with a spot UPCR (or UACR) shows no abnormal proteinuria (ie, UPCR <200 mg/g [23 mg/mmol] or UACR <30 mg/g [3.4 mg/mmol]), then we attribute the initial positive urine dipstick to either transient proteinuria or a false positive test result (eg, due to a highly concentrated urine sample). In such patients, clinicians should repeat the urinalysis one or two more times to confirm that proteinuria is not persistent. If proteinuria is present on future examinations, the patient should be evaluated for persistent proteinuria. (See 'Transient proteinuria' above.)

●Abnormal proteinuria – If quantification with a spot UPCR (or UACR) shows abnormal proteinuria (ie, UPCR ≥200 mg/g [23 mg/mmol] or UACR ≥30 mg/g [3.4 mg/mmol]), our approach is as follows:

•If the patient is <30 years old, we exclude the possibility of orthostatic (postural) proteinuria. Orthostatic proteinuria is characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine. It is a relatively common finding in adolescents but an uncommon disorder in adults over the age of 30 years. The evaluation for orthostatic proteinuria is presented in detail separately. (See "Orthostatic (postural) proteinuria".)

If orthostatic proteinuria is diagnosed, we would monitor kidney function and proteinuria annually for evidence of progression. If orthostatic proteinuria is excluded, we evaluate the patient for persistent isolated proteinuria, as detailed below.

•If the patient is ≥30 years old, we consider the patient to have persistent isolated proteinuria (see 'Isolated proteinuria' above). Such patients should be referred to nephrology for further evaluation and management. Such evaluation may involve additional laboratory testing and possibly a kidney biopsy to obtain a more definitive diagnosis. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults", section on 'Indications for a nephrology evaluation'.)

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 kidney protective. By contrast, isolated non-nephrotic proteinuria may have a much more indolent course, although a fraction of such patients eventually develop kidney function impairment. In patients with chronic kidney disease (CKD), even low-level proteinuria is associated with poor kidney and general outcomes. In a cohort of mainly White patients with CKD and a baseline estimated glomerular filtration (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 [39].

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 [40]. At a mean of 5.8 years, proteinuria disappeared in 23 percent, and 11 percent developed kidney function impairment, which was defined as a creatinine clearance <60 mL/min and/or a serum creatinine >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) [41].

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 in detail separately. (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".)

SCREENING FOR PROTEINURIA — 

Annual screening for proteinuria is not cost effective in the general population of healthy individuals under age 60 years [42]. By contrast, early detection of proteinuria may be cost-effective in high-risk patients (eg, older individuals or those with diabetes, hypertension, chronic kidney disease, or autoimmune disease [eg, systemic lupus erythematosus]) 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 without diabetes. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of antihypertensive drugs on albuminuria' and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'ACE inhibitors or ARBs' and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus", section on 'ACE inhibitors or ARBs'.)

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 5^th to 6^th 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 10^th to 12^th 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

●Normal and abnormal protein excretion – Most healthy adults excrete <150 mg/day of protein in the urine. The normal rate of albumin excretion is <20 mg/day. Persistent albumin excretion between 30 and 300 mg/day is called moderately increased albuminuria (formerly called “microalbuminuria”). Persistent albumin excretion >300 mg/day is considered overt proteinuria or severely increased albuminuria (formerly called “macroalbuminuria”). (See 'Normal and abnormal protein excretion' above.)

●Types of proteinuria – There are four basic types of proteinuria: glomerular, tubular, overflow, and postrenal proteinuria (table 1). (See 'Types of proteinuria' above.)

●Detection or proteinuria – Two semiquantitative methods are available to screen patients for proteinuria. These are the urine dipstick and the precipitation of urine proteins with sulfosalicylic acid (SSA). If abnormal proteinuria is suggested by either technique, the proteinuria should be quantified. (See 'Urine dipstick' above and 'Sulfosalicylic acid test' above.)

●Measurement of proteinuria – Urine protein excretion can be measured as either total protein or albumin. There are three methods to quantify proteinuria: 24-hour urine collection, spot urine protein-to-creatinine ratio (UPCR), and spot urine albumin-to-creatinine ratio (UACR).

•The 24-hour urine collection is the gold standard for measuring protein excretion, but it is cumbersome for patients and often collected incorrectly. (See '24-hour urine collection' above.)

•The spot UCPR and UACR are the preferred methods for estimating urine total protein and urine albumin excretion, respectively. 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 in the ratio) and therefore by total daily creatinine production, and urine protein excretion can vary throughout the day. (See 'Urine protein-to-creatinine ratio' above and 'Urine albumin-to-creatinine ratio' above.)

●Approach to the adult with proteinuria – The initial evaluation of patients with a positive urine dipstick for protein includes a targeted history, physical examination, and laboratory testing to identify potential causes and to determine whether further evaluation and referral to a specialist (nephrology) is warranted. (See 'Initial evaluation' above.)

•In patients who have any associated signs and symptoms concerning for glomerular disease (eg, foamy urine, edema, gross hematuria, systemic symptoms), urine findings suggestive of glomerular disease (eg, dysmorphic red blood cells [RBCs], specifically acanthocytes; RBC casts; and white blood cells [WBCs] or WBC casts in the absence of infection), or evidence of kidney function impairment (elevated serum creatinine or reduced estimated glomerular filtration rate [eGFR]), we refer to nephrology for further evaluation and management. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

•In patients who have no associated symptoms, no urine findings suggestive of glomerular disease, and normal kidney function, we take the following approach (see 'All other patients' above):

-If quantification with a spot UPCR or UACR shows no abnormal proteinuria, then we attribute the initial positive urine dipstick to either transient proteinuria or a false positive test. We repeat the urinalysis one or two more times to confirm that proteinuria is not persistent. If proteinuria is present on future examinations, the patient should be evaluated for persistent proteinuria. (See 'Transient proteinuria' above.)

-If quantification with a spot UPCR or UACR shows abnormal proteinuria and the patient is <30 years old, we exclude the possibility of orthostatic (postural) proteinuria. If orthostatic proteinuria is diagnosed, we monitor kidney function and proteinuria annually for evidence of progression. If orthostatic proteinuria is excluded, we evaluate the patient for persistent isolated proteinuria. (See "Orthostatic (postural) proteinuria".)

-If quantification with a spot UPCR or UACR shows abnormal proteinuria and the patient is ≥30 years old, we consider the patient to have persistent isolated proteinuria. Such patients should be referred to nephrology for further evaluation and management. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)