INTRODUCTION — Orthostatic (also referred to as postural) proteinuria is characterized by an elevated protein excretion while in the upright position and normal protein excretion in a supine or recumbent position. It is the most frequent cause of isolated proteinuria in children, especially adolescents.

The prevalence, pathogenesis, diagnosis, and prognosis of orthostatic proteinuria will be reviewed here. The evaluation of proteinuria in children is discussed separately. (See "Evaluation of proteinuria in children".)

DEFINITION

Normal protein excretion — The following are definitions for normal protein excretion in children and adults:

●Children – Urinary protein excretion in the normal child is less than 100 mg/m² per day (<4 mg/m² per hour) or a total of 150 mg per day. (See "Evaluation of proteinuria in children", section on 'Normal protein excretion'.)

●Adults – Urinary protein excretion in the normal adult is less than 50 mg per eight-hour duration or a total of 150 mg per day. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Amounts of proteinuria'.)

EPIDEMIOLOGY — Orthostatic proteinuria accounts for 60 percent of all childhood cases of persistent daytime proteinuria, and 75 percent of proteinuria in adolescent patients [1-5] (see "Evaluation of proteinuria in children"). However, it is uncommon in adults over 30 years of age. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Rule out orthostatic proteinuria'.)

The actual prevalence of pediatric orthostatic proteinuria is uncertain. The best estimate is based on a 2015 cross-sectional study of 1701 schoolaged children and adolescents between 6 and 15 years of age that reported orthostatic proteinuria was detected in 11 students (0.7 percent of the cohort) [5]. In this study, proteinuria was initially detected on a first random urine in 64 participants (3.7 percent of the cohort) that persisted in repeated samples in only 16 individuals including the 11 with orthostatic proteinuria.

PATHOGENESIS — The mechanisms responsible for orthostatic proteinuria are not well understood. The following theories, which are not mutually exclusive, have been proposed [4]:

●Normal variant

●Subtle glomerular abnormality

●Exaggerated hemodynamic response to the upright position

●Left renal vein entrapment

Normal variant — Protein excretion normally increases with assumption of the upright posture from a recumbent position, although total protein excretion typically remains within the normal range [6]. Thus, orthostatic proteinuria may, in at least some cases, be an exaggeration of the normal response.

Subtle glomerular abnormality — In some patients with orthostatic proteinuria, renal biopsies have shown subtle glomerular changes, such as focal mesangial hypercellularity or basement membrane thickening [7-9]. These minor changes coupled with a glomerular hemodynamic abnormality could result in orthostatic proteinuria.

Exaggerated hemodynamic response to the upright position — Increases in norepinephrine and angiotensin II when assuming an upright position may enhance glomerular permeability in susceptible individuals [10]. Angiotensin II release may also be associated with left renal vein entrapment (referred to as Nutcracker syndrome).

Because orthostatic proteinuria is benign and typically abates spontaneously with age, there is no clinical role for angiotensin blockade. (See 'Prognosis' below.)

Left renal vein entrapment — Observations from several small case studies or reports suggest that entrapment of the left renal vein by the aorta and superior mesenteric artery (referred to as Nutcracker syndrome) plays a role in the pathogenesis of orthostatic proteinuria [11-14].

●Thirteen of 15 Japanese children with orthostatic proteinuria had left renal vein entrapment on ultrasonography, compared with only 9 of 80 control school children [13]. Of the nine control children with left renal vein entrapment, six had normal protein excretion, although orthostatic proteinuria was present in the other three.

●Left renal vein flow abnormalities by Doppler ultrasonography were detected in 30 of 47 Korean children with orthostatic proteinuria compared with no left renal vein flow abnormalities in 27 healthy controls [14].

●Renal ultrasound with Doppler flow imaging in 24 Italian and Swiss children with orthostatic proteinuria showed left renal vein entrapment in 18 [12]. During follow-up, orthostatic proteinuria resolved in half of the patients within 2 to 15 years of diagnosis [15]. There were no differences in clinical features between those in whom the proteinuria did and did not resolve other than a tendency for an increased body mass index (BMI) for age and gender in those who resolved. It was hypothesized that a higher BMI may increase space between the aorta and the superior mesenteric artery, thus freeing the previously entrapped left renal vein.

The Nutcracker phenomenon has also been implicated in the development of microscopic or gross hematuria, primarily in children in Asia and Europe. (See "Evaluation of gross hematuria in children", section on 'Asymptomatic hematuria' and "Evaluation of microscopic hematuria in children", section on 'Nutcracker syndrome'.)

CLINICAL PRESENTATION — Individuals with orthostatic proteinuria are generally asymptomatic and are diagnosed incidentally when a urinalysis is done for an unrelated condition or as part of routine care [4].

DIAGNOSIS — The diagnosis of orthostatic proteinuria is made by demonstrating that urinary protein excretion is normal while in a recumbent position, and increased while upright. The two approaches generally used to make the diagnosis of orthostatic proteinuria are:

●Comparison of the protein-to-creatinine (Pr/Cr) ratio in urine samples collected in recumbent and upright positions. This is the most convenient standard method.

●24-hour urine collection divided into separate daytime and nighttime collections.

Urine protein-to-creatinine ratio — Comparison of the Pr/Cr ratio in urine samples collected in the recumbent and upright position is the easiest way to establish a diagnosis. Orthostatic proteinuria is confirmed if the recumbent urine sample has a normal Pr/Cr ratio and the upright sample has an elevated ratio. A normal urine Pr/Cr ratio is <0.2 mg protein/mg creatinine (<20 mg protein/mmol creatinine) in adults and children greater than two years of age, and <0.5 mg protein/mg creatinine (<50 mg protein/mmol creatinine) in infants and toddlers age 6 to 24 months. (See "Evaluation of proteinuria in children", section on 'Quantitative assessment' and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

The easiest recumbent sample to obtain is the first morning void. The patient should void completely just before going to sleep and collect a morning sample as soon as arising. A second sample is then collected after at least an hour of being upright and moving around normally.

A normal urine Pr/Cr ratio on the first morning void and an elevated ratio on the second specimen confirm the diagnosis of orthostatic proteinuria.

24-hour urine collection — Alternatively, a split 24-hour urine collection can be used to make the diagnosis of orthostatic proteinuria. This approach is generally used if the diagnosis remains uncertain after comparison of urine Pr/Cr ratios on recumbent and upright urine samples. This test should be deferred for at least 24 hours after strenuous exercise.

The following protocol is used (table 1), which can be printed out and given to the patient (see "Patient education: Split urine collection for orthostatic proteinuria (Beyond the Basics)"):

●The timing of the daytime collection begins with the first morning void. This void is discarded, however, and not included in the collection since it represents urine produced prior to the timed collection period.

●Daytime collection – After the first morning void is discarded, all subsequent voids are collected throughout the day as the patient performs his/her normal activities. The collection ends with inclusion of a final void that is collected immediately prior to going to bed. It is important that the times of the discarded first morning void and the final void before bedtime be noted so that the duration of the daytime collection is known.

●Nighttime collection – The nighttime (recumbent) collection consists of any urine voided during the nighttime after going to bed and also includes the next morning's first void collected immediately upon awakening. The collection ends with this void. The time of the first morning void should be noted so that the duration of the nighttime collection is also known.

Total urinary protein excretion rate in mg/hour is then determined for both the daytime and nighttime collections by dividing total protein content in each collection by the time of that collection in hours. For children, this rate should then be normalized to body surface area in square meters.

Orthostatic proteinuria is diagnosed if the urinary protein excretion rate is normal for the nighttime collection (for children <4 mg/m² per hour and for adults <50 mg over an eight-hour period) and the daytime collection exceeds the normal protein excretion rate.

Urinary dipstick — The urinary dipstick is often used to screen for proteinuria, but in dilute specimens the degree of proteinuria may be underestimated. With a urine specific gravity >1.010 (which is generally the case with first morning void specimens from patients with normal urinary concentrating mechanisms who do not drink overnight), it may be the simplest and cheapest test to demonstrate normal urine protein excretion in a first morning sample [4]. However, if there is uncertainty regarding the urinary dipstick result, a urine Pr/Cr ratio should be calculated.

Effect of strenuous exercise on the diagnostic evaluation — A relatively short period (15 to 20 minutes) of maximal exercise can lead to increased proteinuria in a substantial number of normal individuals. The increase in proteinuria is proportional to the intensity of exercise, and even a short period of intense physical activity can lead to a rise in proteinuria [16]. As a result, to avoid the risk of a false positive result, in the setting of recent strenuous exercise, a repeat urine sample should be assessed at least 24 hours after such exercise, and strenuous exercise needs to be avoided for a day before further diagnostic urine testing for proteinuria [17,18].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of orthostatic proteinuria includes conditions that result in either transient or persistent proteinuria (table 2).

●Transient proteinuria – In children, transient proteinuria is the most common cause of a positive urinary dipstick for protein [3]. It is associated with conditions that may alter renal hemodynamics such as acute febrile illness, vigorous exercise, or exposure to extreme cold. This benign condition is distinguished from orthostatic proteinuria as transient proteinuria resolves completely when the underlying condition is no longer present, whereas orthostatic proteinuria is a persistent condition. (See "Evaluation of proteinuria in children", section on 'Approach to the child with proteinuria' and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Rule out transient proteinuria'.)

●Persistent or fixed proteinuria is differentiated from orthostatic proteinuria by elevated protein excretion in urine samples collected in both the recumbent and upright positions. Non-orthostatic persistent proteinuria is a marker for renal parenchymal disease, can be associated with chronic kidney disease, and always warrants further evaluation and follow-up in both children and adults. (See "Glomerular disease: Evaluation in children" and "Evaluation of proteinuria in children", section on 'Approach to the child with proteinuria' and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Persistent isolated proteinuria'.)

It is particularly important to differentiate non-orthostatic persistent proteinuria with its risk for renal disease from orthostatic proteinuria. Making the correct diagnosis of orthostatic proteinuria prevents unnecessary and costly investigation in patients with daytime proteinuria [4].

PROGNOSIS — Orthostatic proteinuria is a benign condition. Long-term follow-up of affected individuals, including data on a small number followed for as long as 40 to 50 years, points to no adverse effect on renal function [5,19,20]. Orthostatic proteinuria also has a tendency to resolve over time. In one study, only 50 percent had persistent orthostatic proteinuria after 10 years of follow-up, with rates further dropping to 17 percent at 20 years [19]. In these studies, all patients had normal renal function, including those with persistent orthostatic proteinuria.

MANAGEMENT AND FOLLOW-UP CARE — In view of the benign course of orthostatic proteinuria, no intervention or further initial evaluation is recommended. Since the long-term prognosis is excellent, the best follow-up care remains unclear. Many pediatric nephrologists recommend that routine health care maintenance of affected individuals include testing a first morning void sample to confirm that it remains free of protein. As noted above, such testing should be deferred for at least 24 hours after strenuous exercise and should not be done during acute illness or fever, or when there may be transient proteinuria ongoing. (See 'Urine protein-to-creatinine ratio' above and 'Effect of strenuous exercise on the diagnostic evaluation' above.)

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)" and "Patient education: Split urine collection for orthostatic proteinuria (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — Orthostatic (also referred to as postural) proteinuria is defined as elevated protein excretion (in children >4 mg/m² per hour and in adults >50 mg over eight hours) while in the upright position and normal protein excretion while in a supine or recumbent position. (See 'Definition' above.)

●Orthostatic proteinuria is the most common cause of isolated proteinuria in children, accounting for 60 percent of all childhood cases of persistent daytime proteinuria. It is uncommon in adults over the age of 30 years. (See 'Epidemiology' above.)

●The underlying pathogenesis for orthostatic proteinuria is not well understood and the proposed mechanisms include variation of normal increased protein excretion while upright, minor glomerular changes, exaggerated hemodynamic response to the upright position, and the presence of left renal vein entrapment resulting in renal venous constriction and increased release of angiotensin II. (See 'Pathogenesis' above.)

●Individuals with orthostatic proteinuria are asymptomatic and generally present due to an incidental finding of a positive urinary dipstick for protein. (See 'Clinical presentation' above.)

●The diagnosis of orthostatic proteinuria is made by showing that the individual's urinary protein excretion is normal while in recumbent position, and increased while upright. (See 'Diagnosis' above.)

•The standard way to make the diagnosis of orthostatic proteinuria is to measure the urine protein to creatinine ratio (Pr/Cr) in two samples: one collected as a first morning void after a period of prolonged recumbency and the other after at least an hour of normal activity in the upright position. The normal value for urine Pr/Cr ratio is <0.2 mg protein/mg creatinine (<20 mg protein/mmol creatinine) in adults and children greater than two years of age, and <0.5 mg protein/mg creatinine (<50 mg protein/mmol creatinine) in infants and toddlers age 6 to 24 months. (See 'Urine protein-to-creatinine ratio' above.)

•Alternatively, a split 24-hour urine collection divided into daytime (upright with normal activity) and nighttime (recumbent and inactive) collections can also be used. (See '24-hour urine collection' above.)

•Urinary dipstick is often the easiest and cheapest test to demonstrate normal protein excretion in a recumbent urine sample. However, it is not a quantitative measure and if there is any uncertainty regarding test results, a urine Pr/Cr measurement should be obtained in the recumbent sample. (See 'Urinary dipstick' above.)

•To avoid false-positive results, testing should be deferred for 24 hours after strenuous exercise, which may increase protein excretion, or during acute illness when there may be transient proteinuria. (See 'Effect of strenuous exercise on the diagnostic evaluation' above and 'Differential diagnosis' above.)

●The differential diagnosis of orthostatic proteinuria includes conditions that result in either transient or persistent proteinuria (table 2). (See 'Differential diagnosis' above.)

•Transient proteinuria, which is associated with fever, vigorous exercise, or exposure to extreme cold, is distinguished from orthostatic proteinuria by the resolution of abnormal daytime protein excretion when the underlying condition is no longer present.

•Persistent proteinuria is differentiated from orthostatic proteinuria by elevated protein excretion in urine samples collected in both the recumbent and upright positions. Non-orthostatic persistent proteinuria is a marker for renal parenchymal disease, can be associated with chronic kidney disease, and always warrants further evaluation and follow-up in both children and adults. (See "Evaluation of proteinuria in children", section on 'Approach to the child with proteinuria' and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Persistent isolated proteinuria'.)

●Orthostatic proteinuria is a benign condition and does not affect renal function. Over time, proteinuria resolves spontaneously in most patients. (See 'Prognosis' above.)

●For individuals with orthostatic proteinuria, we recommend no further initial evaluation or intervention (Grade 1C). Although the long-term prognosis is excellent, we suggest periodic monitoring of protein excretion using a first morning void to reconfirm the diagnosis of orthostatic proteinuria in those who continue to have daytime proteinuria (Grade 2C). (See 'Management and follow-up care' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John T Herrin, MBBS, FRACP, who contributed to an earlier version of this topic review.