Proteinuria

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Chapter 36 PROTEINURIA

Theodore X. O’Connell

General Discussion

Most healthy children excrete small amounts of protein in the urine, which is called physiologic proteinuria. Physiologic proteinuria varies with age and the size of the child. When corrected for body surface area, the protein excretion is highest in newborn infants and decreases with age until late adolescence, when adult levels are reached. Asymptomatic or isolated proteinuria is defined as proteinuria not associated with any signs or symptoms of renal disease. The estimated prevalence of isolated asymptomatic proteinuria in children is between 0.6% and 6.3%. However, only 0.1% of children have persistent proteinuria.

In general, the finding of proteinuria does not warrant an extensive work-up. The finding of proteinuria must be confirmed on two or three more occasions. Transient proteinuria, the most common cause in children, can be induced by a variety of factors, including fever and exercise. The finding of at least two positive urine tests out of three specimens suggests persistent proteinuria and warrants additional evaluation. Orthostatic proteinuria occurs when urine protein excretion occurs in the upright position but returns to normal when the patient is recumbent.

The diagnostic evaluation of the child with dipstick-positive proteinuria is affected by the presence or absence of symptoms. Isolated asymptomatic proteinuria on a urine dipstick, without hematuria, hypertension, or signs of systemic illness or stress, is detected in about 15% of adolescent patients. Only about a fourth of patients have a second dipstick positive for protein if reevaluated within 48 hours, and an even smaller percentage remain positive if tested serially over 6 to 12 months. Therefore, the first step in the evaluation of a child or adolescent with isolated proteinuria is to determine whether the patient has persistent proteinuria in at least two of three urine samples tested 1 or more weeks apart.

Once the diagnosis of persistent proteinuria is established, the physician should determine whether the patient has orthostatic (postural) proteinuria. Orthostatic proteinuria accounts for about 60% of children with persistent proteinuria. The patient is instructed to empty the bladder at bedtime, and in the morning a urine sample is immediately collected, which is then tested for protein. Another urine sample is obtained later in the day after ambulation. If the morning urine samples are negative or show trace protein while ambulatory ones are 1+ or greater, a diagnosis of orthostatic proteinuria is made, and no further evaluation is required. However, a urine protein-creatinine ratio should be measured and blood pressure obtained yearly for children diagnosed with orthostatic proteinuria.

If the patient has persistent, nonorthostatic proteinuria, a more thorough evaluation is warranted. This includes quantification of proteinuria using either a 24-hour urine collection or a urine protein-creatinine ratio on a spot sample. The urine protein-creatinine ratio has become the preferred method because it is more reliable than 24-hour urinary protein measurements. In adults and children over 2 years of age, a urine protein-creatinine ratio lower than 0.2 on a random urine specimen obtained during the day is considered normal. In children aged 6 to 24 months, the upper limit of normal is 0.5. A ratio above 3.0 is consistent with nephrotic-range proteinuria.

The symptomatic child requires more aggressive clinical evaluation. Symptoms may be nonspecific (fever, malaise), more specific but nonurinary (arthritis, rash), or urinary specific (edema, hypertension). The underlying disorder may be renal in origin or secondary to a systemic disease. Children with heavy proteinuria and edema should be evaluated promptly for nephrotic syndrome and, if it is present, have consultation with a pediatric nephrologist. Children with non–nephrotic-range persistent proteinuria who present with hypertension, an abnormal urinalysis, or an elevated plasma creatinine concentration should be evaluated by a pediatric nephrologist.

Figure 36-1 provides an algorithm for the evaluation of pediatric proteinuria.

image

Figure 36-1 Evaluation of pediatric proteinuria.

(From Mahan JD, Turman MA, Mentser MI. Evaluation of hematuria, proteinuria, and hypertension in adolescents. Pediatr Clin North Am 1997;44:1573–1589.)

Causes of Proteinuria

Benign persistent proteinuria

Orthostatic (postural) proteinuria

Transient proteinuria

• Abdominal surgery
• Congestive heart failure
• Emotional stress
• Epinephrine administration
• Extreme cold exposure
• Fever
• Hypovolemia
• Seizures
• Strenuous exercise

Glomerular proteinuria

• Alport syndrome
• Congenital nephrotic syndrome
• Diabetes mellitus
• Focal segmental glomerulonephritis
• Henoch-Schönlein purpura
• Hepatitis B virus-associated nephropathy
• Human immunodeficiency virus (HIV)-associated nephropathy
• IgA nephropathy
• Lupus glomerulonephritis
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis
• Minimal change nephrotic syndrome
• Postinfectious glomerulonephritis

Tubulointerstitial proteinuria

• Chronic interstitial nephritis
• Cystinosis
• Heavy metal poisoning
• Medications (antibiotics, antineoplastic agents)
• Obstructive uropathy
• Polycystic kidney disease
• Pyelonephritis
• Reflux nephropathy
• Renal dysplasia
• Toxins
• Wilson’s disease

Key Historical Features

Recent history of fever, strenuous exercise, dehydration, emotional distress, or exposure to cold

Recent upper respiratory infection

Gross hematuria

Change in weight

Change in urine output

Symptoms of a systemic illness

• Fevers
• Arthralgias
• Arthritis
• Skin rash

Hearing loss

Medical history, especially recurrent urinary tract infections (UTIs)

Surgical history

Medications

Family history, especially familial renal disease

Key Physical Findings

Vital signs, especially blood pressure

Measurement of height and weight

General assessment of physical condition

Cardiopulmonary examination

Abdominal examination for ascites and to palpate the kidneys

Extremity examination for edema or arthritis

Skin examination for rash, purpura, or pallor

Suggested Work-up

Repeat urine dipstick two or three additional times To determine whether proteinuria is persistent
Perform urine dipstick on a morning urine sample and a sample later in the day To determine whether orthostatic proteinuria is the cause

If orthostatic proteinuria is diagnosed, the child should be reevaluated annually with measurement of blood pressure and urine protein-creatinine ratio. If fixed isolated proteinuria is diagnosed, the work-up depends on the degree of proteinuria. If the urine protein-creatinine ratio is less than 1.0, twice-yearly visits, later extended to annual visits, with determination of the urine protein-creatinine ratio are sufficient. If proteinuria persists beyond 1 year, referral to a pediatric nephrologist for renal biopsy should be considered. If the urine protein-creatinine ratio is greater than 1.0, the following evaluation should be considered:

Microscopic urinalysis To evaluate the urinary sediment for hematuria, bacteria, casts, or eosinophils
Serum blood urea nitrogen (BUN) and creatinine To evaluate renal function
Serum electrolytes To evaluate for electrolyte disturbances
Serum albumin and total protein Serum albumin is decreased in nephrotic syndrome
Complete blood count (CBC) To evaluate for infection. Anemia may indicate chronic renal disease.
Serum cholesterol and triglycerides Cholesterol is increased in nephrotic syndrome
Complement C3 and C4 levels Levels are decreased in the glomerulonephritides
Renal ultrasound To help detect anatomic or congenital abnormalities, especially in children under 6 years of age

Additional Work-up

Antistreptolysin O (ASO) titer and/or streptozyme test If postinfectious glomerulonephritis is suspected by history. Referral to a pediatric endocrinologist is recommended for most cases of postinfectious glomerulonephritis.
Antinuclear antibody (ANA) If systemic lupus erythematosus is suspected
Hepatitis B and C serologies If hepatitis B or C infections are suspected
HIV testing If HIV infection is suspected
Voiding cystourethrogram May be indicated if there is a history of recurrent UTIs or if a renal ultrasound reveals scarring
Renal biopsy May be indicated when laboratory tests are abnormal and a glomerular disease is suspected
Referral to a pediatric nephrologist See text for some indications. Generally indicated if renal biopsy is needed, if the patient has hematuria with symptoms of renal disease, if nephrotic-range proteinuria is diagnosed, or if the diagnosis is unclear.

References

1. Hogg R.J., et al. National Kidney Foundation’s kidney disease outcomes initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 2003;111:1416–1421.

2. Hogg R.J. Adolescents with proteinuria and/or the nephrotic syndrome. Adolesc Med Clin. 2005;16:163–172.

3. Loghman-Adham M. Evaluating proteinuria in children. Am Fam Physician. 1998;58:1145–1152.

4. Mahan J.D., Turman M.A., Mentser M.I. Evaluation of hematuria, proteinuria, and hypertension in adolescents. Pediatr Clin North Am. 1997;44:1573–1589.

5. Patel H.P. The abnormal urinalysis. Pediatr Clin North Am. 2006;53:325–337.

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