Pediatric Annals

Special Issue Article 

Proteinuria in Children

Daniel Ranch, MD

Abstract

Although the American Academy of Pediatrics (AAP) removed the screening urinalysis from its health supervision guidelines in 2007, the use of the urinalysis remains an important part of pediatric care. Thus, the incidental finding of proteinuria is still commonplace when a urine sample is collected for various complaints, such as fever and abdominal pain. Knowing when to reassure a patient with proteinuria versus when to perform additional testing is a situation that general practitioners face regularly, but also one that not all may be comfortable dealing with due to the possibility of missing a diagnosis. In addition, proteinuria in certain conditions can signify renal disease and worse outcomes, so general practitioners should know how to screen and interpret the results. Understanding the common benign and pathological causes of proteinuria helps medical providers to better inform and treat their patients, and possibly avoid unnecessary additional testing or subspecialty referrals. [Pediatr Ann. 2020;49(6):e268–e272.]

Abstract

Although the American Academy of Pediatrics (AAP) removed the screening urinalysis from its health supervision guidelines in 2007, the use of the urinalysis remains an important part of pediatric care. Thus, the incidental finding of proteinuria is still commonplace when a urine sample is collected for various complaints, such as fever and abdominal pain. Knowing when to reassure a patient with proteinuria versus when to perform additional testing is a situation that general practitioners face regularly, but also one that not all may be comfortable dealing with due to the possibility of missing a diagnosis. In addition, proteinuria in certain conditions can signify renal disease and worse outcomes, so general practitioners should know how to screen and interpret the results. Understanding the common benign and pathological causes of proteinuria helps medical providers to better inform and treat their patients, and possibly avoid unnecessary additional testing or subspecialty referrals. [Pediatr Ann. 2020;49(6):e268–e272.]

Proteinuria, or abnormal levels of total protein in the urine, is a common finding in children. Large studies in school children have shown that up to approximately 10% have isolated proteinuria found in a single random urine sample.1,2 However, most of these children were found to have transient proteinuria, with persistent proteinuria on subsequent samples being found in just a small percentage of those studied. Due to the recognition that transient proteinuria was not associated with adverse outcomes, and the poor cost-effectiveness of screening urinalysis in children, the American Academy of Pediatrics recommended abandoning this practice.3 Nevertheless, persistent proteinuria is a harbinger of underlying renal disease and is associated with worse clinical outcomes.4 Understanding the different etiologies and the evaluation process of proteinuria in children is important for clinicians (Figure 1).

Evaluation of persistent proteinuria in children. ANA, antinuclear antibody; BP, blood pressure; BUN, blood urea nitrogen; Cr, creatine; hx, history. Adapted from Hogg et al.6

Figure 1.

Evaluation of persistent proteinuria in children. ANA, antinuclear antibody; BP, blood pressure; BUN, blood urea nitrogen; Cr, creatine; hx, history. Adapted from Hogg et al.6

The nephron is the functional unit of the kidneys, consisting of the glomerulus and renal tubule. The glomerular filtration barrier, which is comprised of the podocyte and its foot processes, the glomerular basement membrane, and the fenestrated capillary endothelium, prevents most proteins from being filtered into the tubular lumen.5 Normally, <150 mg/day of total protein in adults or <100 mg/m2/day in children is excreted into the urine. This total protein consists of Tamm-Horsfall protein (∼50%), albumin (<30%), with the remainder made up of immunoglobulins, tubular proteins, and other low molecular weight proteins.6

Albuminuria, which is what urine dipsticks detect, is indicative of underlying glomerular pathology. Disturbances in any component of the glomerular filtration barrier can lead to increased glomerular permeability and abnormal protein excretion. However, more evidence indicates that abnormal pathology of the podocyte and the slit diaphragm may be the key mechanisms.5 Additionally, disruption of normal mechanisms in tubular protein reabsorption, or overwhelming of the filtration and tubular systems by excess proteins in the plasma, can also lead to abnormal protein excretion.

Definitions

Urine dipstick testing, the most common technique used to identify proteinuria, detects mostly albumin in the urine, and so the terms “proteinuria” and “albuminuria” are frequently used interchangeably, despite the different technical definitions. Macroalbuminuria (>300 mg/24 hours) is typically detected by routine dipstick testing because the threshold for total protein detection is approximately 20 mg/dL. However, microalbuminuria (30–300 mg/24 hours) is not detected by routine dipstick testing and requires a more sensitive urine test such as the urine microalbumin to creatinine ratio (UACR) (Table 1). Nephrotic range proteinuria is defined as >1,000 mg/m2/day or >2–3 g/day. The nephrotic syndrome is characterized by nephrotic range proteinuria, hypoalbuminemia, edema, and hyperlipidemia.6

Cutoffs for Protein in Urine in Children

Table 1.

Cutoffs for Protein in Urine in Children

Etiology

Proteinuria in children can be classified into transient, orthostatic, or persistent proteinuria. Persistent proteinuria is further categorized as glomerular, tubular, or overflow proteinuria.

Transient Proteinuria

Transient proteinuria is a common cause of isolated proteinuria in children. In a mass screening program in Korea, approximately 20% of school children with isolated proteinuria were found to have transient proteinuria.7 It is usually associated with an acute illness such as fever or seizure, or with recent vigorous exercise.8,9 Some evidence suggests that this may be due to stimuli-induced expression of CD80 in podocytes, leading to podocyte foot process effacement, disruption of the slit diaphragm complex, and proteinuria.10 Clinically, transient proteinuria resolves on its own and is not associated with adverse clinical outcomes, so further evaluation is not needed.

Orthostatic Proteinuria

Orthostatic proteinuria is a common cause of isolated proteinuria, especially in the healthy adolescent. The classic presentation is an asymptomatic child who has mild proteinuria on a random urine sample but has no proteinuria on a sample collected at the first-morning void. The exact underlying cause is unknown, and it may be a normal variant versus minor subtle underlying glomerular abnormalities or exaggerated hemodynamic response in the upright position. Alternatively, some data support “nutcracker syndrome,” where the left renal vein is compressed between the superior mesenteric artery and aorta as a possible mechanism.11 However, these patients usually present with gross hematuria and abdominal or flank pain. Orthostatic proteinuria has a benign long-term prognosis, and frequently self-resolves over time.12

Persistent Proteinuria

Persistent proteinuria is proteinuria found on two or more first-morning samples; in children, this is typically due to glomerular disease, especially with nephrotic range proteinuria (Table 2). Tubulointerstitial etiologies include acute interstitial nephritis, toxic nephropathies, or Fanconi syndrome. Overflow proteinuria can be due to excess amounts of low molecular weight proteins in the plasma, such as in rhabdomyolysis, hemolysis, or plasma cell dyscrasias. Persistent microalbuminuria has been shown to predict renal disease in patients with diabetes mellitus, cardiovascular disease, obesity, and the metabolic syndrome.13

Causes of Proteinuria in Children

Table 2.

Causes of Proteinuria in Children

Evaluation and Diagnosis

Proteinuria used to be a frequent incidental finding when routine urine screening was performed at well-child visits. Now, it is most likely found during evaluation for another ailment, such as abdominal pain or edema. Thus, the clinical context during which the proteinuria is discovered is of the utmost importance.

Urine dipstick testing is the most frequent method used during the initial detection of proteinuria. Albumin in the urine sample reacts with tetrabromophenol blue on the test strip, resulting in a color change from yellow to green to blue, with increasing amounts of protein present. A result of >1+ is abnormal, and a persistent finding of >1+ warrants further evaluation.14 False-positive results for proteinuria via dipstick testing may be due to an alkaline or concentrated urine specimen; however, these traditional beliefs have been challenged recently.15 Additionally, visibly bloody urine, exposure of the sample to disinfectants/detergents, or iodinated contrast agents, may also cause a false-postive result. False-negative results could be due to a dilute urine specimen or nonalbumin proteinuria. In the past, sulfosalicylic acid precipitation was used to confirm the presence of protein in a urine sample; however, this test is not used anymore because it is no more accurate than the current dipstick tests.

The gold standard for quantification of daily urine protein excretion remains the 24-hour urine collection. However, it is a cumbersome test to perform in children, especially in those who are not yet toilet trained. The advent of the random urine protein to creatinine ratio (UPCR), which has been found to closely estimate the urine protein excretion in a 24-hour collection, has obviated the need for this collection as a first-line investigation.16,17 However, a first-morning urine specimen for the UPCR is ideal, because protein excretion throughout the day is variable; it is also used to rule out orthostatic proteinuria as well. A UPCR of <0.2 mg protein/mg creatinine (<0.5 in children age 6–24 months) is considered normal. A UPCR >2 implies nephrotic range proteinuria. To detect microalbuminuria (lower levels of albuminuria), a first-morning urine specimen can be collected to calculate the UACR. A result of >30 to 300 mg albumin/g creatinine is considered abnormal.6 When obtaining a 24-hour urine collection, the creatinine level should be measured as well. This is used to calculate the creatinine excretion and determine whether the sample collection was adequate. In general, daily creatinine excretion is approximately 15 to 20 mg/kg/day in women and 20 to 25 mg/kg/day in men.18

Clinical clues to a possible underlying disease process should guide additional testing. Proteinuria and edema suggest nephrotic syndrome, and blood should be tested for hypoalbuminemia, hyperlipidemia, blood urea nitrogen, and creatinine. Hypertension, edema, and hematuria indicates glomerulonephritis; therefore, kidney function tests, electrolytes, and complement (C3, C4) levels should be measured. If systemic diseases such as systemic lupus erythematosus (SLE) or antineutrophil cytoplasmic antibody (ANCA) vasculitis are suspected, then the proper serologic studies (anti-nuclear antibody, anti-double stranded DNA antibody, anti-neutrophil cytoplasmic antibodies) should be sent. A renal ultrasound is a relatively inexpensive and noninvasive study to help detect anatomic abnormalities, such as a solitary kidney, renal hypoplasia/dysplasia, mass, or sometimes renal scarring.

Treatment

Determination of the underlying cause directs the optimal therapies in patients with proteinuria. As stated previously, transient and orthostatic proteinuria do not require additional evaluation or treatment. Minimal change disease is the most common cause of idiopathic nephrotic syndrome in children.19 These patients are treated empirically with systemic steroids, without an initial renal biopsy. Prednisone/prednisolone can be given at a dose of 60 mg/m2/day for 4 weeks, then decreased to alternate day dosing at 40 mg/m2/day for 4 weeks, and then discontinued. Current data have not shown any advantage of longer treatment duration.20 Most patients have remission of their nephrotic syndrome, defined as a trace or negative urine protein dipstick result for 3 consecutive days, by 2 to 4 weeks of daily therapy. Those who do not enter remission with this treatment course should be referred to a nephrologist for further evaluation and possible diagnostic kidney biopsy. Minimal change disease has a good overall long-term prognosis, and most morbidity is from immunosuppressive treatments. Other causes of nephrotic syndrome, such as focal segmental glomerulosclerosis or membranous nephropathy, typically do not respond well to steroid treatment and require long-term care due to the high risk of progression to kidney failure.21

Patients with glomerulonephritis, either suspected isolated renal disease (eg, membranoproliferative glomerulonephritis, immunoglobulin A nephropathy) or part of a systemic disease (eg, systemic lupus erythematosus, ANCA vasculitis), should be referred to a nephrologist and appropriate specialists for diagnostic kidney biopsy and long-term care, because they also have a significantly increased risk of progression to kidney failure plus extra-renal comorbidities. Patients with microalbuminuria related to underlying diabetes mellitus should be started on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, because remission of proteinuria has been shown to delay or even reverse diabetic kidney disease progression.22

Conclusions

Proteinuria in children is a frequent finding despite the change in practice recommendations, and the initial discovery can be concerning for both the family and the medical provider. Establishing whether it is persistent versus transient or orthostatic proteinuria will help to determine the optimal diagnostic evaluation and treatment. Early recognition of more serious underlying disease processes enables patients to receive the appropriate therapies in a timely manner.

References

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  6. Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J. Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics. 2000;105(6):1242–1249. doi:10.1542/peds.105.6.1242 [CrossRef] PMID:10835064
  7. Park YH, Choi JY, Chung HS, et al. Hematuria and proteinuria in a mass school urine screening test. Pediatr Nephrol. 2005;20(8):1126–1130. doi:10.1007/s00467-005-1915-8 [CrossRef] PMID:15947990
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  11. Vehaskari VM. Mechanism of orthostatic proteinuria. Pediatr Nephrol. 1990;4(4):328–330. doi:10.1007/BF00862510 [CrossRef] PMID:2206899
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  13. Erkan E. Proteinuria and progression of glomerular diseases. Pediatr Nephrol. 2013;28(7):1049–1058. doi:10.1007/s00467-012-2335-1 [CrossRef] PMID:23124512
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  16. Houser M. Assessment of proteinuria using random urine samples. J Pediatr. 1984;104(6):845–848. doi:10.1016/S0022-3476(84)80478-3 [CrossRef] PMID:6726514
  17. Abitbol C, Zilleruelo G, Freundlich M, Strauss J. Quantitation of proteinuria with urinary protein/creatinine ratios and random testing with dipsticks in nephrotic children. J Pediatr. 1990;116(2):243–247. doi:10.1016/S0022-3476(05)82881-1 [CrossRef] PMID:2299494
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Cutoffs for Protein in Urine in Children

Testing method Normal Proteinuria Nephrotic range
24-hour urine collection <100 mg/m2/day ≥100 mg/m2/day >1,000 mg/m2/day
Spot urine protein/creatinine ratio (mg/mg) <0.5 (children 6–24 months) <0.2 (children >2 years old) ≥0.5 (children age 6–24 months) ≥0.2 (children >2 years old) >2
Spot urine microalbumin/creatinine ratio (mg/gm) <30 - -

Causes of Proteinuria in Children

<list-item>

Transient

  Idiopathic

  Fever

  Recent strenuous exercise

</list-item><list-item>

Orthostatic proteinuria

</list-item><list-item>

Persistent proteinuria

Glomerular disease

   Nephrotic syndrome

    Minimal change disease

    Focal segmental glomerulosclerosis

    Membranous nephropathy

   Immune-mediated nephritis

    Membranoproliferative glomerulone-phritis

    Immunoglobulin A nephropathy

    Systemic lupus erythematosus

    Infection-related nephritis (hepatitis B/C, HIV)

   Glomerular injury

    Diabetic nephropathy

    Reflux nephropathy

    Chronic kidney disease

Tubulointerstitial disease

  Allergic interstitial nephritis

  Toxic nephropathy (drugs, heavy metals)

  Fanconi syndrome

  Pyelonephritis

Overflow

  Multiple myeloma

  Rhabdomyolysis

  Hemolysis

</list-item>
Authors

Daniel Ranch, MD, is an Associate Professor, Department of Pediatrics, University of Texas Health Science Center at San Antonio.

Address correspondence to Daniel Ranch, MD, University of Texas Health Science Center at San Antonio, Department of Pediatrics, 7703 Floyd Curl Drive, San Antonio, TX 78229; email: ranch@uthscsa.edu.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/19382359-20200520-04

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