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
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.
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
Tubular proteinuria
Results from increased excretion of low molecular weight proteins such as beta-2-microglobulin, alpha-1microglobulin, and retinol-binding protein
Tubulointerstitial diseases, can lead to increased excretion of these smaller proteins
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
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
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
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
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
Recent infection
Weight changes
Presence of edema
Symptoms of hypertension
Gross hematuria
Changes in urine output
Dysuria
Skin lesions
Swollen joints
Abdominal pain
Previous abnormal urinalysis
Growth history
Medications
Family history
Renal disease, hypertension, deafness, visual disorders
Vital signs
Inspect for presence of edema, pallor, skin lesions, skeletal deformities
Screening for hearing and visual abnormalities
Abdominal exam
Lung exam
Cardiac exam
Single urine positive for protein
Obtain:
1) first morning void Pr/Cr
2) UA in office
Pr/Cr and UA normal
Pr/Cr normal,
UA positive
Both specimens abnormal
Transient
Proteinuria
Orthostatic
Proteinuria
Persistent
Proteinuria
Follow-up routinely
Patient should have a repeat urinalysis on a first morning void in one year
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
1.
2.
3.
4.
5.
6.
7.
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
Renal ultrasound
Serum complement levels (C3 and C4)
ANA
Streptozyme testing,
Hepatitis B and C serology
HIV testing
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
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.
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
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