EVALUATION OF ASYMPTOMATIC PROTEINURIA IN CHILDREN By: Patricia Baile

MECHANISMS OF PROTEIN HANDLING BY KIDNEY Glomerular capillary wall permits passage of small molecules while restricting macromolecules

3 components of glomerular wall Endothelial cell Basement membrane Epithelial cell

MECHANISMS OF PROTEIN HANDLING BY KIDNEY Glomerular permeability Steric hindrance: due to spatial alignment of the passing molecules, relative to membrane pores Viscous drag: impedance to movement caused by fluid lining the pores Electrical hindrance: due to electrostatic repulsion between epithelial surface and plasma proteins

MECHANISMS OF PROTEIN HANDLING BY KIDNEY Normal protein excretion affected by interplay of glomerular and tubular mechanisms Glomerular injury: abnormal losses of intermediate MW proteins like albumin Tubular damage: increased losses of low MW proteins

NORMAL PROTEIN EXCRETION Child: < 100mg/m2/day or 150mg/day Neonates: up to 300mg/m2

ABNORMAL PROTEIN EXCRETION Urinary protein excretion in excess of 100 mg/m2 per day or 4 mg/m2 per hour Nephrotic range proteinuria (heavy proteinuria) is defined as ≥ 1000 mg/m2 per day or 40 mg/m2 per hour.

ABNORMAL PROTEIN EXCRETION Glomerular proteinuria Due to increased filtration of macromolecules May result from glomerular disease (most often minimal change disease) or from nonpathologic conditions such as fever, intensive exercise, and orthostatic (or postural) proteinuria

ABNORMAL PROTEIN EXCRETION Tubular proteinuria Results from increased excretion of low molecular weight proteins such as beta-2-microglobulin, alpha-1- microglobulin, and retinol-binding protein Tubulointerstitial diseases, can lead to increased excretion of these smaller proteins

ABNORMAL PROTEIN EXCRETION Overflow Proteinuria Results from increased excretion of low molecular weight proteins due to marked overproduction of a particular protein to a level that exceeds tubular reabsorptive capacity

ASYMPTOMATIC PROTEINURIA Levels of protein excretion above the upper limits of normal for age No clinical manifestations such as edema, hematuria, oliguria, and hypertension

MEASUREMENT OF URINARY PROTEIN 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

MEASUREMENT OF URINARY PROTEIN Sulfosalicylic acid test Detects all proteins in the urine including the low molecular weight proteins that are not detected by the dipstick Performed by mixing one part urine supernatant (eg, 2.5 mL) with three parts 3 percent sulfosalicylic acid, followed by assessment of the degree of turbidity

MEASUREMENT OF URINARY PROTEIN Quantitative assessment Children with persistent dipstick-positive proteinuria must undergo a quantitative measurement of protein excretion, most commonly on a timed 24-hour urine collection In children: levels >100 mg/m2 per day (or 4 mg/m2 per hour) are abnormal Proteinuria of greater than 40 mg/m2 per hour is considered heavy or in the nephrotic range

MEASUREMENT OF URINARY PROTEIN Quantitative assessment Alternative method of quantitative assessment is measurement of the total protein/creatinine ratio (mg/mg) on a spot urine sample, preferably the first morning specimen For children >2 yrs: normal value for this ratio is <0.2 mg protein/mg creatinine For infants and children <2yrs: <0.5 mg protein/mg creatinine

CAUSES OF ASYMPTOMATIC PROTEINURIA

TRANSIENT PROTEINURIA Most common cause Can occur in association with fever, seizures, strenuous exercise, emotional stress, hypovolemia, extreme cold, epinephrine administration, abdominal surgery, or congestive heart failure Believed to be glomerular in origin, related to hemodynamic changes (decreased renal plasma flow) rather than altered permeability of capillary wall

ORTHOSTATIC PROTEINURIA Increase in protein excretion in the erect position compared with levels measured during recumbency Proteinuria usually does not exceed 1-1.5 gm/day Mechanism postulated to involve an increased permeability of the glomerular capillary wall and a decrease in renal plasma flow Long-term studies have documented the benign nature of this condition, with recorded normal renal function up to 50 years later

PERSISTENT PROTEINURIA Present for long periods after initial detection Absence of both orthostatic proteinuria and clinical evidence of renal disease Clinical course may be benign May be secondary to parenchymal disease

DIFFERENTIAL DIAGNOSES OF PERSISTENT PROTEINURIA Benign proteinuria Acute Glomerulonephritis, mild Chronic Glomerular Disease that can lead to nephrotic syndrome Chronic nonspecific glomerulonephritis Chronic interstitial nephritis Congenital and acquired structural abnormalities of urinary tract

EVALUATION OF ASYMPTOMATIC PROTEINURIA

HISTORY Recent infection Weight changes Presence of edema Symptoms of hypertension Gross hematuria Changes in urine output Dysuria Skin lesions

HISTORY Swollen joints Abdominal pain Previous abnormal urinalysis Growth history Medications Family history Renal disease, hypertension, deafness, visual disorders

PHYSICAL EXAMINATION Vital signs Inspect for presence of edema, pallor, skin lesions, skeletal deformities Screening for hearing and visual abnormalities Abdominal exam Lung exam Cardiac exam

LABORATORY EVALUATION Single urine positive for protein 1) first morning void Pr/Cr 2) UA in office Obtain: Pr/Cr and UA normal Transient Proteinuria Pr/Cr normal, UA positive Orthostatic Proteinuria Both specimens abnormal Persistent Proteinuria

TRANSIENT PROTEINURIA Follow-up routinely Patient should have a repeat urinalysis on a first morning void in one year

ORTHOSTATIC PROTEINURIA Perform Orthostatic Test CBC BUN Creatinine Electrolytes 24-hr urine excretion < 1.5g/day  repeat UA and blood work in 1 year > 1.5g/day  refer to Pediatric Nephrologist

Instructions for Testing for Orthostatic Proteinuria Patient voids at bedtime. Discard urine. No food or fluids after dinner until the next morning. When patient awakes in the morning, urine specimen is collected prior to arising, or after as little ambulation as possible. Label specimen #1. Child should ambulate for the next 2 to 3 hours. Then collect specimen. Label specimen #2. Both specimens should be tested by dipstick or sulfosalicylic acid. Specimen #1 should be concentrated with a specific gravity of at least 1.018. If specimen #1 is free of protein and specimen #2 has protein, then the test is positive for orthostatic proteinuria. If both specimens have protein, orthostatic proteinuria is unlikely and further evaluation is necessary. This protocol should be repeated on at least 2 occasions to confirm the diagnosis.

FURTHER EVALUATION OF PERSISTENT PROTEINURIA Examination or urine sediment CBC Renal function tests (blood urea nitrogen and creatinine) Serum electrolytes Cholesterol Albumin and total protein

OTHER TESTS Renal ultrasound Serum complement levels (C3 and C4) ANA Streptozyme testing, Hepatitis B and C serology HIV testing

PERSISTENT PROTEINURIA If further work-up normal, urine dipstick should be repeated on at least two additional specimens. If these subsequent tests are negative for protein, the diagnosis is transient proteinuria. If the proteinuria persists or if any of the studies are abnormal, the patient should be referred to a pediatric nephrologist Urinary protein excretion should be quantified by a timed collection

INDICATIONS FOR RENAL BIOPSY Many nephrologists recommend close monitoring for those children with urinary protein excretion below 500 mg/m2 per day before considering a biopsy Monitoring should include assessment of blood pressure, protein excretion, and renal function. If any of these parameters shows evidence of progressive disease, a renal biopsy should be performed to establish a diagnosis.

MANAGEMENT Avoid excessive restrictions in child’s lifestyle Dietary protein supplementation is of no benefit Salt restriction unnecessary and potentially dangerous No indication for limitation of activity Importance of compliance with regular follow-up should be stressed

REFERENCES UpToDate Feld L, Schoeneman M, Kaskel F: Evaluation of the Child with Asymptomatic Proteinuria. Pediatrics in Review 1984; 5: 248-254 Nelson’s Textbook of Pediatrics

QUESTIONS?