Pediatric Annals

The Evaluation of the Child With Proteinuria

Robert B Ettenger, MD

Abstract

Proteinuria is probably the most common laboratory finding of renal disease.1 It is, in fact, the hallmark of many renal diseases. However, appreciable amounts of protein may be present in the urine of otherwise completely healthy children and adolescents. In most children evaluated for proteinuria, it is discovered as a chance finding.

The challenge to the practicing pediatrician and pediatric nephrologist is to differentiate the proteinuric child with renal disease from the otherwise well child. This needs to be done in an efficient, costeffective manner. To do this, the clinician must have an understanding of the mechanisms by which excess protein may enter the urine, the criteria for the detection of excess proteinuria, and the clinical situations in which proteinuria can be expected.

MECHANISMS OF PROTEINURIA

Glomerular Proteinuria

The glomerular capillary loop serves as a filter that proteins must traverse to enter the urine. Molecules with a radius of less than 20 A units freely pass the glomerular wall, while the filter significantly hinders the movements of molecules with a radius of 45 to 50 A. Albumin, with a radius of 36 A, is hindered only moderately by its size in its passage across the basement membrane.

Were size the only barrier; significant amounts of albumin would be filtered from the blood. However, there is a second and probably more important barrier. The glomerular basement membrane and its associated cellular processes bear large amounts of negatively charged molecules. These negative charges repel and decrease the filtration of negatively charged macromolecules, such as albumin. Many plasma proteins are negatively charged at physiologic pH, but the charge-dependent restriction of albumin is quantitatively of greatest importance.

Damage to the glomerulus can be envisioned to either distort the pores of the size-selective filter2 or remove any of the resident negative charges.3 The resulting glomerular proteinuria is composed primarily of albumin. Alteration of pore size is felt to be the mechanism responsible for proteinuria in some forms of glomerulonephritis. Removal of resident negative charges appears to be present in some forms of nephrotic syndrome.

Tubular Proteinuria

Under normal conditions, small amounts of protein, ie, albumin and small molecular weight proteins, cross the glomerular capillary wall. In the absence of renal tubular dysfunction, most of the filtered protein is reabsorbed in the proximal tubule.1 Only the small amount of protein that escapes tubular reabsorption ultimately appears in the urine of normal individuals. With sufficient tubular damage, however, normal protein reabsorption does not occur. The urine contains an increased amount of low molecular weight protein such as be ta2 -microglobulin and lysozyme.

Other Mechanisms of Proteinuria

Hemodynamic alterations of glomerular blood flow can cause proteinuria without any structural glomerular abnormality.4 Hemodynamic changes can influence passage of solute (in this case, protein) across the glomerular membrane by both convection and diffusion. "Convection" occurs when solute is carried across a membrane in the company of fluid, while "diffusion" of a solute occurs down a concentration grathent independently of fluid movement.

Individuals with chronic renal failure have decreased numbers of functioning nephrons, which leads to increased filtration rates in the remaining nephrons. This in turn is associated with an increased transglomerular protein loss by convection.4·5 This is the likely explanation for the proteinuria that is present in advanced nonglomerular renal disease, eg, polycystic kidney disease. An increased diffusion of protein occurs in some recipients of repeated transfusions of albumin, so-called "overflow proteinuria."

DETECTION OF PROTEINURIA

Qualitative

While there are numerous methods to detect protein in the urine,6 the dipstick has emerged as the most "user-friendly" and consequently, the method most commonly used by clinicians. The dipstick measures the concentration of…

Proteinuria is probably the most common laboratory finding of renal disease.1 It is, in fact, the hallmark of many renal diseases. However, appreciable amounts of protein may be present in the urine of otherwise completely healthy children and adolescents. In most children evaluated for proteinuria, it is discovered as a chance finding.

The challenge to the practicing pediatrician and pediatric nephrologist is to differentiate the proteinuric child with renal disease from the otherwise well child. This needs to be done in an efficient, costeffective manner. To do this, the clinician must have an understanding of the mechanisms by which excess protein may enter the urine, the criteria for the detection of excess proteinuria, and the clinical situations in which proteinuria can be expected.

MECHANISMS OF PROTEINURIA

Glomerular Proteinuria

The glomerular capillary loop serves as a filter that proteins must traverse to enter the urine. Molecules with a radius of less than 20 A units freely pass the glomerular wall, while the filter significantly hinders the movements of molecules with a radius of 45 to 50 A. Albumin, with a radius of 36 A, is hindered only moderately by its size in its passage across the basement membrane.

Were size the only barrier; significant amounts of albumin would be filtered from the blood. However, there is a second and probably more important barrier. The glomerular basement membrane and its associated cellular processes bear large amounts of negatively charged molecules. These negative charges repel and decrease the filtration of negatively charged macromolecules, such as albumin. Many plasma proteins are negatively charged at physiologic pH, but the charge-dependent restriction of albumin is quantitatively of greatest importance.

Damage to the glomerulus can be envisioned to either distort the pores of the size-selective filter2 or remove any of the resident negative charges.3 The resulting glomerular proteinuria is composed primarily of albumin. Alteration of pore size is felt to be the mechanism responsible for proteinuria in some forms of glomerulonephritis. Removal of resident negative charges appears to be present in some forms of nephrotic syndrome.

Tubular Proteinuria

Under normal conditions, small amounts of protein, ie, albumin and small molecular weight proteins, cross the glomerular capillary wall. In the absence of renal tubular dysfunction, most of the filtered protein is reabsorbed in the proximal tubule.1 Only the small amount of protein that escapes tubular reabsorption ultimately appears in the urine of normal individuals. With sufficient tubular damage, however, normal protein reabsorption does not occur. The urine contains an increased amount of low molecular weight protein such as be ta2 -microglobulin and lysozyme.

Other Mechanisms of Proteinuria

Hemodynamic alterations of glomerular blood flow can cause proteinuria without any structural glomerular abnormality.4 Hemodynamic changes can influence passage of solute (in this case, protein) across the glomerular membrane by both convection and diffusion. "Convection" occurs when solute is carried across a membrane in the company of fluid, while "diffusion" of a solute occurs down a concentration grathent independently of fluid movement.

Individuals with chronic renal failure have decreased numbers of functioning nephrons, which leads to increased filtration rates in the remaining nephrons. This in turn is associated with an increased transglomerular protein loss by convection.4·5 This is the likely explanation for the proteinuria that is present in advanced nonglomerular renal disease, eg, polycystic kidney disease. An increased diffusion of protein occurs in some recipients of repeated transfusions of albumin, so-called "overflow proteinuria."

DETECTION OF PROTEINURIA

Qualitative

While there are numerous methods to detect protein in the urine,6 the dipstick has emerged as the most "user-friendly" and consequently, the method most commonly used by clinicians. The dipstick measures the concentration of protein in the urine. The reagent area is impregnated with tetrabromophenol blue; reactions with amino groups cause a color change. Albumin causes the tetrabromophenol blue to change color far more readily than other proteins,7 so the dipstick method should be regarded as specific for albuminuria.

Tetrabromophenol blue is a pH indicator. The dipstick is buffered so that it will not change color when the urine pH is in the normal range. However, at a urine pH of 7 or above, the dipstick will register falsely positive.8 Other causes of a false-positive dipstick reaction for protein are listed in Table 1. Overlong immersion and placing the reagent portion of the dipstick directly in the urine stream can cause leaching of the pH buffer on the strip with the tetrabromophenol blue, making the indicator dye more likely to change color.

Table

TABLEICauses of False-Positive Dipstick Reactions for Urinary Protein

TABLEI

Causes of False-Positive Dipstick Reactions for Urinary Protein

A urine sample is considered positive for protein if it registers 1 + (30 mg/dL) or more in a urine whose specific gravity is ^1.015. If the urine's specific gravity is > 1.015, the dipstick must be 2+ (100 mg/dL) or greater to be considered positive. When the urine is too dilute (eg, < 1.005), significant amounts of protein can be diluted out and the test interpreted as a false negative. A child is considered to have persistent proteinuria by qualitative measurement if the dipstick registers positive by the above definition in at least two of three random urine specimens collected 1 or more weeks apart.9

Other qualitative methods are available for the determination of proteinuria, although they are not as convenient as the dipstick. The most commonly used of these are the turbidometric methods, which precipitate proteins at an acid pH. Reagents include sulfosalicylic acid, trichloracetic acid, nitric acid, or sodium sulfate. In contrast to the dipstick method, the sulfosalicylic acid methods detects all forms of proteinuria, raise-positive results can be produced by radiographic contrast material, large doses of penicillin or penicillin analogues, cephalosporin, sulfonamide metabolites, and high uric acid concentrations in the urine.6

Quantitative

Because qualitative testing for proteinuria is relatively imprecise, a timed urine collection for protein quantitation is essential to establish the presence and degree of proteinuria.

In adults, a protein excretion of up to 150 mg per 24 hours is considered within normal limits. In children and adolescents, there are varying published figures for the upper limit of normal, ranging from 60 mg to 288 mg in 24 hours.10·11 The variations can be minimized to some extent by correcting for body surface area because there is a correlation between body size and protein excretion.4 As shown in Table 2, when factored in this way, protein excretion varies little among children in different age groups. Neonates represent an exception, with premature infants having the highest basal protein excretion.4,11

Table

TABLE 224-Hour Urine Protein Excretion for Children of Different Ages*

TABLE 2

24-Hour Urine Protein Excretion for Children of Different Ages*

Using body surface area and a precisely timed 12- to 24-hour urine collection, the following guideline can also be used to assess protein excretion912:

* normal: ^4 mg/m2/hour,

* abnormal: 4 to 40 mg/m2/hour, and

* nephrotic: >40 mg/m2/hour.

In clinical practice, it is often difficult to obtain reliable timed urine collections. The collection of 24-hour urine samples to measure protein excretion necessarily imposes a delay to the diagnostic work-up, and more importantly, it often yields inaccurate results because of collection errors. To circumvent this difficulty, a random urine specimen can be analyzed for both protein and creatinine concentration. The ratio of the urine protein (in milligrams) to the urine creatinine (in milligrams) (UPr/Cr) is strongly correlated with the 24-hour urine protein excretion.13

In adults, random single urine specimens obtained during daytime activities from normal control subjects have a UPr/Cr ratio of <0.2. In children over 2 years of age, a ratio of 0.2 or less also can be considered normal,14 although some have extended the upper limit of normal to 0.25.4 For children aged 6 months to 2 years, the upper limit of normal should be considered 0.5. 14 The upper limit ratio value of 0.2 to 0.25 for children >2 years of age is valid for both recumbent and upright random urine specimens, although protein excretion by UPr/Cr ratio in the upright position is higher than in recumbency.15 Postexercise specimens probably should not be used routinely because the upper limit of normal values is dramatically higher in these specimens than in urine specimens obtained in the recumbent or upright position.15

There are some important caveats to the use of the UPr/Cr ratio as an estimate of quantitative protein excretion. Because serum and urinary creatinine are dependent on muscle mass, this technique is not valid in children with severe nutritional problems. Also, it is unclear whether the UPr/Cr ratio can be used in children with low levels of renal function since tubular secretion may produce a disproportionately high urine creatinine level in these patients. Nevertheless, the UPr/Cr ratio has great usefulness in most clinical situations.16

EPIDEMIOLOGY OF PROTEINURIA

Proteinuria may be seen commonly in pediatric practice, particularly in adolescents. Prevalence figures will vary based on the definition of abnormal proteinuria that is used. Most proteinuria is transient or intermittent, so that studies that examine more than one specimen per patient are more likely to detect proteinuria. If 1 + proteinuria is considered positive with the dipstick, as many as 10% of schoolaged children will test positively for proteinuria at some time.4,17 The prevalence falls to approximately one quarter of this if the definition is tightened to require two of four specimens with 1 + proteinuria.17 Only about 1 in 1000 have proteinuria in all four specimens. Most children who meet the criteria of proteinuria on initial testing lose their proteinuria over time after several subsequent urines are tested.9 Only about 10% of children persist with proteinuria after 6 to 12 months of follow-up.9,18

The prevalence of proteinuria is highly age dependent. There is a gradual rise, with a peaking in adolescence. The rise in boys lags behind that in girls by approximately 3 years.4 The peak prevalence is reached at 13 years of age in girls and at 16 years of age in boys.10 Following this peak, there is a decline, with lower prevalence figures in young adults.4

ETIOLOGY OF PROTEINURIA

Proteinuria is the hallmark of many renal diseases. Often, the type and severity of underlying disease is obvious from the accompanying signs and symptoms, eg, edema and hypertension. More often for the pediatrician, the child presents with asymptomatic proteinuria.

Table

TABLE 3Classification and Etiologies of Proteinuria in Children and Adolescents

TABLE 3

Classification and Etiologies of Proteinuria in Children and Adolescents

FunctiomuTTransient Proteinuria

Functional proteinuria typically is transient and clears when the inciting factor remits or is removed. The degree of proteinuria rarely registers over 2 + on the dipstick. Causes of functional proteinuria are outlined in Table 3.

Febrile proteinuria was found in one study in about 6% of 196 hospitalized children.19 It usually appears with the onset of fever and resolves by the 10th to 14th day, even if fever disappears earlier.6·19 Subsequent febrile episodes (ie, within a week of the original attack) usually are not accompanied by proteinuria.

Proteinuria, like hematuria, may occur after exercise. The degree of hematuria or proteinuria seems to correlate with the duration and severity of the exercise.20 Studies conducted by Houser et al15 suggest that an increase in proteinuria, specifically in the UPr/Cr ratio, is a common occurrence after exercise in normal children. The proteinuria of exercise abates within 48 hours of cessation of exercise.

It is likely that the transient proteinuria seen with fever, exercise, and congestive heart failure is due to hemodynamic alterations in glomerular blood flow. This leads to increased diffusion of protein across the glomerular basement membrane.1,4

Orthostatic Proteinuria

On standing, protein excretion is increased, even in normal subjects excreting normal amounts of protein in 24 hours.15,21 In patients with proteinuric renal disease, the proteinuria is accentuated in the upright posture. True orthostatic proteinuria is defined as abnormally high protein excretion in the upright position only.

Orthostatic proteinuria accounts for 60% of all proteinuria seen in children; the figure is even higher in adolescents.9 Up to 16 years of age, girls have a higher incidence of orthostatic proteinuria than boys. As a rule of thumb, children with orthostatic proteinuria excrete no more than 1 g of protein in 24 hours. In some patients, orthostatic proteinuria is fixed and reproducible, while in others it is only transient or intermittent. AU of these variations appear to have a good prognosis.

While orthostatic proteinuria appears to be the result of an excessive glomerular filtration of protein, there is no clear-cut explanation of the mechanism or mechanisms that underlie this phenomenon. Suggestions include altered renal hemodynamics, partial renal vein obstruction, and the effect of circulating immune complexes.1,4

In young adults, follow-up for as long as 50 years has indicated a benign clinical course.22,23 The common clinical impression among pediatric nephrologists is that the prognosis in pediatric patients is similarly good. However, there is a paucity of prospective long-term studies in children and adolescents with orthostatic proteinuria. A relatively short-term study found minimal renal biopsy abnormalities in children with this condition.17 Thus, available evidence, although limited for children, strongly suggests a uniformly benign prognosis for isolated orthostatic proteinuria. It is important to remember, however, that if hematuria or excessive proteinuria coexists with proteinuria in an orthostatic pattern, underlying renal disease may well be present.

Persistent Asymptomatic Isolated Proteinuria

Isolated proteinuria is defined as an abnormally high level of proteinuria in an otherwise healthy child whose clinical and laboratory work-up uncovers no other abnormalities.4 A true persistent pattern, ie, proteinuria in 100% of urine specimens tested, is rare in children.17 A more reasonable definition is when 80% or more of urine specimens, including recumbent specimens, are found to contain abnormal amounts or concentrations of protein.6

Many studies suggest that the majority of asymptomatic children and adolescents with persistent isolated proteinuria do not have progressive renal disease.17,24,25 In these studies, renal biopsy reveals either normal histology or mild nonspecific glomerular alterations. Other studies report results that are somewhat divergent. Of 65 children with isolated proteinuria who underwent biopsy, 55 had normal renal histology.26 The other 10 children, whose biopsies were obtained 9 months to 9 years after the onset of proteinuria, had findings of focal glomerulosclerosis. Five of these 10 developed moderate renal failure or end-stage renal disease from 2 1Zz to 10 years after the discovery of the proteinuria.

More recently, Yoshikawa et al27 reviewed the results of renal biopsies performed in 53 children with constant isolated proteinuria. The patients' mean age was 8 years old, and the biopsies were performed approximately 2 to 3 years after proteinuria was discovered. Forty-seven percent of the patients had significant glomerular abnormalities, and 15 of these (28% of the entire group of 53) had focal glomerulosclerosis. Other diseases discovered on biopsy included IgA nephropathy, membranous glomerulopathy, and diffuse mesangial proliferative glomerulonephritis. Chronic renal failure developed in 7 of the 15 patients with focal glomerulosclerosis. No factor, including the magnitude of the proteinuria at the time of the biopsy, had any predictive value for significant glomerular changes. After approximately 61Zz years, 60% of all patients continued to have asymptomatic, constant, isolated proteinuria, irrespective of whether they had manifested major glomerular abnormalities on biopsy. However, slightly more than one third of children with normal glomerular histology lost their proteinuria during the follow-up period; only 12% of the patients with major abnormalities developed protein-free urine in the same follow-up period.

What is one to make of the conflicting data about isolated asymptomatic persistent proteinuria? Informed opinion is clearly divided. Some state that the prognosis is excellent and use the term "constant benign PrOtCmUrIa" to describe this entity.9 Others are more circumspect and view the entity of persistent nonorthostatic proteinuria with caution, even though their data suggest that this entity is associated with only minimal biopsy changes.4,17 Still others view this entity with alarm.27 This latter view is bolstered by data from adults, which indicate a somewhat unfavorable long-term prognosis.28 There is also concern that experimental studies suggest focal glomerulosclerosis may be the outcome of long-term unremitting proteinuria.29

Clearly, patients with isolated asymptomatic persistent proteinuria form a heterogeneous group. Some of the studies group together orthostatic proteinuria (with its good prognosis) and isolated persistent proteinuria. It is probably important to distinguish these two entities. Even when authors attempt to rigorously segregate isolated persistent proteinuria for study, there is difficulty in comparing studies. Vehaskari and Rapóla,17 for example, found that only one of their almost 9000 patients had abnormal proteinuria in 100% of urine specimens. On the other hand, Yoshikawa et al27 identified 53 children who had abnormal protein concentrations in 6 of 6 tested urine specimens. The former group had only minor glomerular abnormalities,17 while the latter group had a relatively large percentage of patients with significant abnormalities.27

Until further well-designed prospective studies are carried out, it seems reasonable to view the prognosis of isolated persistent proteinuria with prudent caution. The level of concern should rise moderately if the proteinuria is unremitting. Even so, any haste to perform a renal biopsy should be tempered with the understanding that our ability to treat the diagnoses that may be discovered on biopsy (eg, focal glomerulosclerosis, IgA nephropathy) still is quite limited.

WORK-UP OF A CHILD OR ADOLESCENT WITH PROTEINURIA

A stepwise approach can be efficient, expeditious, and cost effective. The work-up outlined here is divided into three phases and assumes that abnormal proteinuria has been discovered and confirmed. The first phase establishes the boundaries of the problem. The second phase focuses on the search for an underlying classification or etiology. The third phase confirms the diagnosis. Phase 1 should always be done by pediatricians and phase II can be carried out by either pediatricians or pediatric nephrologists, while phase III is the province of pediatric nephrologists.

Phase I Work-Up

The phase I work-up begins with a complete history and physical examination. The primary care phystcian should look carefully for indications of underlying renal disease such as a family history of renal disease, edema, hypertension, short stature, etc.

Table

TABLE 4When to Refer a Child With Proteinuria*

TABLE 4

When to Refer a Child With Proteinuria*

Next, the primary care physician should obtain an early morning urinalysis, including both dipstick and microscopic analysis. Special attention should be paid to the presence of hematuria, since the coexistence of hematuria and proteinuria suggests the diagnosis of glomerulonephritis.

In addition, ambulatory and recumbent dipstick urinalyses for proteinuria should be obtained. This initial screen for orthostatic proteinuria consists of dipstick testing of samples collected immediately on arising and after several hours of routine ambulation. The child must have emptied his or her bladder before going to sleep the night before. A typical finding in orthostatic proteinuria is a negative or trace result in the recumbent specimen but 1 + or greater on the upright specimen.

Phase II Work-Up

Laboratory values for serum electrolytes, creatinine, albumin, cholesterol, and blood urea nitrogen should be determined. The primary care physician should determine if antistreptococcal antibodies are present, as well as the complement level (usually C3) and antinuclear antibody.

A renal ultrasound should be performed. At this point, a voiding cystourethrogram is needed only if there is an abnormality on the ultrasound or if there is a history of febrile urinary tract infections.

Timed 12-hour urine collections for protein quantitation, both recumbent and ambulatory, should be obtained. This is the definitive test for orthostatic proteinuria. It is performed when the dipstick readings in the Phase I work-up are both equivocal or ^l + . This study also can be performed earlier in rhe work-up to validate an abnormal UPr/Cr ratio. Performing the test in the following way definitively establishes or discards the diagnosis of orthostatic proteinuria; it also allows precise quantitation of the 24-hour urine protein excretion by adding the results of the back-to-back collections:

* Have the child void and discard the urine just prior to going to bed. Note the exact time.

* Collect the urine produced during the night by voiding into a container marked "recumbent" immediately on arising. Record the time. Record both the starting and ending times of recumbency on the containers.

* Collect all urine produced during the day up to and including the specimen voided just prior to retiring (at the same time as the urine had been discarded the previous night). Label the containers "Ambulatory." Record the start time as the time when the "Recumbent" specimen was voided; the end time is recorded as the time of voiding prior to retiring.

Table

TABLE 5lndications for Renal Biopsy in a Child With Proteinuria*

TABLE 5

lndications for Renal Biopsy in a Child With Proteinuria*

A normal result is <4 mg/m2/hour in the "Recumbent" specimen. Normally, and with orthostatic proteinuria, this is less than 100 mg to 150 mg of protein, depending on the child's age. The protein excretion in the "Ambulatory" collection may vary, but for the diagnosis of orthostatic proteinuria it should be 2 to 4 times that found in the "Recumbent" collection. The 24-hour protein excretion should be ^l g for the diagnosis of orthostatic proteinuria. Should the urine excretion exceed 200 mg in the "Recumbent" collection or contain an amount in the "Recumbent" collection equal to the abnormally increased protein excretion in the "Ambulatory" collection, the patient does not have orthostatic proteinuria, and further work-up is indicated.9

Phase III Work-Up

Table 4 lists a series of situations that suggest underlying renal disease may be present. At this stage, referral to a pediatric nephrologist is appropriate.9

The pediatric nephrologist usually will perform more specific testing to establish the exact diagnosis. This often will entail the performance of a percutaneous renal biopsy. Indications for a renal biopsy in a child with proteinuria are listed in Table 5.6

There is no hard-and-fast rule about if and when a renal biopsy should be performed with persistent, asymptomatic nonorthostatic proteinuria that is truly isolated. The recommendation in Table 5 should be viewed as quite flexible. If proteinuria is present in . 100% of all urine specimens examined or if it is relatively heavy (eg, 30 to 40 mg/m2/hour), it may be reasonable to consider performing a renal biopsy after a shorter period of time (eg, 6 months). With proteinuria that remains at only 2 or 3 times the normal amount, the biopsy probably can be deferred indefinitely as long as there is good clinical follow-up.

There are a large number of unusual causes of proteinuria in the child, and an experienced pediatric nephrologist may be required to identify the etiology in obscure cases.6 However, the large majority of cases can be dealt with by the primary care physician with, at most, pediatric nephrology consultation. It is important that in these situations, long-term followup be continuous and complete. The long-term prognosis for some of these conditions is by no means completely clear, and individual follow-up is important. If asymptomatic proteinuria disappears, the frequency of follow-up visits can be decreased markedly. This will occur in the majority of patients. Proteinuria continuing or increasing over several years probably merits renal biopsy. Currently, there is little in medicines armamentarium for many of the diseases that may be discovered by biopsy. However, as new therapies for glomerulonephritis and focal glomerulosclerosis evolve, it will become increasingly more important to identify the child with these conditions.

REFERENCES

1. Hostetter TH. Proteinuria. The Kidney. 1987;20:13-18.

2. Myers BtA Okarma TB, Friedman S, et al. Mechanisms of proteinuria in human glomerular nephritis. J Cfc» invest. 1982;70:732-746.

3. Bridges CR, Myers BD, Brenner BM, Deen WM. Glomerular change alteration in human minimal change nephropathy: Kidney Int. 1982;22:677-684.

4- Vehaskari VM, Rohson AM. Proteinuria. In: Edelman CM Jr, ed. Pediatric Kidney Disease. Boston, Mass: Little, Brown & Co; 1992:531 -551.

5. Rohson AM, Mor J, Root ER, et al. Mechanism of proteinuria in nonglomerular renal disease. Kidney Int. 1979;16:416-429.

6. Ettenger RB. Workup of the child with proteinuria. In: Lieberman E. ed. ClnucoJ Pediatric Nephrology- Philadelphia, Pa: JB Lippincott Co; 1976:27-44.

7. Bowie L, Smith S, Gochman N. Characteristics of binding between reagent strip indicators and urinary protein. CIm Chem. 1977;23:128-130.

8. Wechsler D, Ibsen L, Fosarelli P. Apparent proteinuria as a consequence of sodium bicarbonate ingestion, ftdialrics. 1990;36:318-319.

9. Norman ME. An office approach to hematuria and proteinuria. Pediatr CIm North Am. 198734:545-560.

10. Wagner MG, Smith FC Jr, Tinglof BO Jr, Comberg E. Epidemiology of proteinuria. J PeaW. 1968;73:825-832.

11. Miltenyi M. Urinary protein excretion in healthy children. Clin Nephrol. I979;12:216221.

12. International Study of Kidney Disease in Children. Nephrotic syndrome in children: a randomized trial comparing two prednisone regimens in steroid-responsive patients who relapse early. J Pediatr. 1979;95:239-243.

13. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine sample to estimate quantitative proteinuria. N Engl.! Med. 1983;309:1543-1546.

14- Houser MT. Assessment of proteinuria using random urine samples. J Pediatr. 1984;104:845-848.

15. Houser MT, John MF, Kbbayoshi A, Walbum J. Assessment of urinary prorein excretion in the adolescent: effect of body position and exercise. J Pediatr. 1986;109:556-561.

16. Abitol C, Zillemelo C, Freundlich M, Strauss J. Quantitations of proteinuria with urinary protein/creatinine ratios and random testing with dipsticks in nephrotic children. J Pediatr. 1990;! 16:243-247.

17. Vehaskari VM, Rapola I Isolated proteinuria: analysis of a school-age population. J Pediatr. 1982;101:661-668.

18. Randolph MF, Greenfield M. Proteinuria: a 6-year study of normal infants, preschool, and school-aged population previously screened for urinary traer disease. Am J Dis Child. 1967;114:631-638.

19. Marks M, McLaine PN, Drummond KN. Proteinuria in children with febrile illnesses. Arch Dis Child. 1970;45:250-253.

20. Poorrmaus JR. Exercise and renal function. Sports Med. 1984;1:125-153.

21. Robinson RR, Glenn WG. Fixed and reproducible proteinuria IV, urinary albumin excretion by healthy human subjects in the recumbent and upright postures. J Lab Clin Med. 1964;34:717-723.

22. Rystand DA, Spreiter S. Prognosis in postural (orthostatic) proteinuria: 40 to 50 year follow-up of six patients after diagnosis by Thomas Addis. N Engl J Med. 1981;205:618-621.

23. Glassock R. Postural proteinuria: no cause for concern. N Engl J Med. 1981 ;305:639641.

24. McLaine PN, Drummond KN. Benign persistent asymptomatic proteinuria in childhood. Pediatrici. 1970;46:548-552.

25. Urizaf RE, Tinglof BO, Smith FG Jr, Mcintosh RM- Persistent asymptomatic proteinuria in children. Am J CBn PaAaI. 1974;62:461 .

26. Habib R, Loirot C. Proteinuria. In: Rover P, Habib R, Mathieu H. Broyer M, eds. Pediatric Nephrology. Philadelphia, Pa: WB Saunders Co; 1974:247.

27. Yoshikawa N, Kitagowa K, Ohta K, Tanaka R, Nakamuria H. Asymptomatic constant isolated proteinuria in children. J Pediatr. 1991;1 10:375-379.

28. Sinniah R, Law CH, Pwee HS. Glomerular lesions in patients with asymptomatic persistent and orthostatic proteinuria discovered on routine medical examination. Clin Nephrol. 1977;7:1-14.

29. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med. 1988318:1657-1666.

TABLEI

Causes of False-Positive Dipstick Reactions for Urinary Protein

TABLE 2

24-Hour Urine Protein Excretion for Children of Different Ages*

TABLE 3

Classification and Etiologies of Proteinuria in Children and Adolescents

TABLE 4

When to Refer a Child With Proteinuria*

TABLE 5

lndications for Renal Biopsy in a Child With Proteinuria*

10.3928/0090-4481-19940901-07

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