EVALUATION OF ASYMPTOMATIC PROTEINURIA IN CHILDREN

1. EVALUATION OF ASYMPTOMATIC PROTEINURIA IN CHILDREN By: Patricia Baile

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

3. 3 components of glomerular wall • Endothelial cell • Basement membrane • Epithelial cell

4. 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

5. 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

6. NORMAL PROTEIN EXCRETION • Normal protein excretion • Child: < 100mg/m2/day or 150mg/day • Neonates: up to 300mg/m2

7. 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.

8. 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

9. 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

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. CAUSES OF ASYMPTOMATIC PROTEINURIA

17. 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

18. 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

19. 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

20. 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

21. EVALUATION OF ASYMPTOMATIC PROTEINURIA

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

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

24. 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

25. LABORATORY EVALUATION

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

27. 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

28. 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.

29. 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

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

31. 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

32. 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.

33. 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

34. 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

35. QUESTIONS?