3. INTRODUCTION
• The demonstration of proteinuria on a routine screening
urinalysis is common
• 10% of children aged 8-15 yr test positive for proteinuria by
urinary dipstick at some time.
• The challenge is to differentiate the child with proteinuria
related to renal disease from the otherwise healthy child with
transient or other benign forms of proteinuria.
4. MECHANISMS OF PROTEIN HANDLING BY
KIDNEY
• Glomerular capillary wall
permits passage of small
molecules while
restricting
macromolecules
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. MECHANISMS OF PROTEINURIA
• Nephrotic syndrome - increased permeability of the glomerular capillary
wall
• On biopsy, the extensive effacement of podocyte foot processes (the hallmark of
idiopathic nephrotic syndrome.
• Idiopathic nephrotic syndrome is associated with complex disturbances in the
immune system, especially T cell– mediated immunity.
• focal segmental glomerulosclerosis -
• a plasma factor produced by a subset of activated lymphocytes.
• mutations in podocyte proteins (podocin, α-actinin 4) and MYH9 (podocyte gene)
• Steroid- resistant nephrotic syndrome - mutations in NPHS2 (podocin)
and WT1 genes, slit pore, and include nephrin, NEPH1, and CD-2
associated protein.
7. MEASUREMENT OF URINARY
PROTEIN
Qualitative
• Urine dipstick
• Sulfosalicylic acid
test
Quantitative
• timed 24-hour
urine collection
• measurement of
the urinary
protein/creatinine
ratio
8. MEASUREMENT OF URINARY
PROTEIN
Urine dipstick
• Offers a qualitative assessment of urinary
protein excretion.
• Primarily detect albuminuria
• less sensitive for other forms of proteinuria
(low molecular weight proteins, Bence
Jones protein, gamma globulins.
9. 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
11. MEASUREMENT OF URINARY
PROTEINUrine dipstick
Will not detect LMW proteins.
False positive –
Very Alkaline sample pH >7.0
contaminated by antiseptic agents
Chlorhexidine or Benzalkonium chloride
Iodinated radiocontrast agents.
Gross hematuria
False Negative –
dilute urine (specific gravity <1.005)
In which the predominant urinary protein is not albumin
12. 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 with three parts 3 percent
sulfosalicylic acid, followed by assessment of the degree of turbidity
13. MEASUREMENT OF URINARY PROTEIN
Quantitative assessment
• most common method - 24-hour urine collection
• Normal protein excretion
• Child: < 100mg/m2/day or 150mg/day
• Neonates: up to 300mg/m2/day
• 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
14. MEASUREMENT OF URINARY PROTEIN
Quantitative assessment
• Alternative method - measurement of the total
protein/creatinine ratio (mg/mg) on a spot urine sample,
• best performed on a first morning voided urine specimen to
eliminate the possibility of orthostatic (postural) proteinuria
• normal protein excretion Ratios
• <0.5 in children <2 yr of age
• <0.2 in children ≥2 yr of age.
• A ratio >2 suggests nephrotic-range proteinuria.
15. 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.
17. ABNORMAL PROTEIN
EXCRETION
•Glomerular proteinuria
• Due to increased filtration of macromolecules
• range from <1 g to >30 g/24 hr
• Glomerular proteinuria should be suspected in any
• patient with a first morning urine protein : creatinine
ratio >1.0, or
• proteinuria of any degree, accompanied by
• hypertension, hematuria, edema, or renal
dysfunction.
19. 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
20. •Transient Proteinuria
• Most common cause
• Usually not exceed 1-2+
• Can occur in association with
• fever >38, 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
ABNORMAL PROTEIN
EXCRETION
21. 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
22. ORTHOSTATIC PROTEINURIA
Most common cause for persistent proteinuria in school aged children
Usually asymptomic
Increase in protein excretion up to 10 fold 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
23. ASYMPTOMATIC PROTEINURIA
•Levels of protein excretion above the upper limits of
normal for age
•No clinical manifestations such as edema,
hematuria, oliguria, and hypertension
24. PERSISTENT PROTEINURIA
• Persons found to have significant proteinuria on a first morning urine
sample on 3 consecutive days
• Indicates renal disease and may be caused by either glomerular or
tubular disorders.
• >1+ on dipstick with urine specific gravity >1.015 or protein :
creatinine ratio >0.2
28. LABORATORY EVALUATION
Single urine
positive for
protein
Obtain:
1) first morning void Pr/Cr
2) UA in 24h urine
Pr/Cr and UA
normal
Transient
Proteinuria
Pr/Cr normal,
UA positive
Orthostatic
Proteinuria
Both specimens
abnormal
Persistent
Proteinuria
29. TRANSIENT PROTEINURIA
• Follow-up routinely
• Patient should have a repeat
urinalysis on a first morning void
in one year
Single urine
positive for
protein
Obtain:
1) first morning void Pr/Cr
2) UA in 24h urine
Pr/Cr and UA
normal
Transient
Proteinuria
Pr/Cr normal,
UA positive
Orthostatic
Proteinuria
Both specimens
abnormal
Persistent
Proteinuria
30. ORTHOSTATIC PROTEINURIA
• Perform Orthostatic Test
• Renal function test
• 24-hr urine excretion
• < 1.5g/day repeat UA and blood work
in 1 year
• > 1.5g/day refer to Pediatric
Nephrologist
Single urine
positive for
protein
Obtain:
1) first morning void Pr/Cr
2) UA in 24h urine
Pr/Cr and UA
normal
Transient
Proteinuria
Pr/Cr normal,
UA positive
Orthostatic
Proteinuria
Both specimens
abnormal
Persistent
Proteinuria
31. INSTRUCTIONS FOR TESTING FOR
ORTHOSTATIC PROTEINURIA
1. Patient voids at bedtime. Discard urine. No food or fluids after dinner until the
next morning.
2. When patient awakes in the morning - specimen #1.
3. Child should ambulate for the next 2 to 3 hours. Then collect specimen. -
specimen #2.
4. Both specimens are tested by dipstick or sulfosalicylic acid.
5. If specimen #1 is free of protein and specimen #2 has protein, then the test is
positive for orthostatic proteinuria.
6. If both specimens have protein, orthostatic proteinuria is unlikely and further
evaluation is necessary.
32. FURTHER EVALUATION OF PERSISTENT
PROTEINURIA
• Examination or urine sediment
• FBC
• Renal function tests (blood urea
nitrogen and creatinine)
• Cholesterol
• Albumin and total protein
Single urine
positive for
protein
Obtain:
1) first morning void Pr/Cr
2) UA in 24h urine
Pr/Cr and UA
normal
Transient
Proteinuria
Pr/Cr normal,
UA positive
Orthostatic
Proteinuria
Both specimens
abnormal
Persistent
Proteinuria
33. OTHER TESTS
• Renal ultrasound
• Serum complement levels (C3 and C4)
• ANA
• Hepatitis B and C serology
• HIV testing
34. 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
35. 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
• Recommendations for renal biopsy.
1. Onset < 6 months of age
2. Initial macroscopic haematuria (without
infection)
3. Persistent microscopic haematuria with
hypertension
4. Renal failure not attributable to
hypovolaemia
5. Persistently low plasma C3, C4 levels
6. Steroid resistance
Renal biopsy is discretionary if:
1. Onset 6-12 months of age
2. Onset above 12 years
3. Persistent hypertension, persistent
microscopic haematuria in isolation
4. Frequently relapsing disease before
commencing on second line drugs
(especially cyclosporin A)
36. 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
37. SUMMARY
• Normal protein excretion
• Child: < 100mg/m2/day or 150mg/day
• Neonates: up to 300mg/m2/day
• Proteinuria of greater than 40 mg/m2 per hour is considered heavy or
in the nephrotic range
• Urine dipstick – qualitative
• 24 hour urine protein, urine Pr/Cr ratio – quantitative
• Abnormal protein excretion - Glomerular proteinuria, Tubular proteinuria, Transient
Proteinuria, Overflow Proteinuria, Orthostatic Proteinuria
• Orthostatic and transient protinuria are benign
• Persistent proteinuria needs further evaluation and disease specific management.
38. REFERENCES
• Nelson’s Textbook of Pediatrics 19th edition
• Illustrated textbook of paediatrics 4th edition
• UpToDate
• National Guidelines of Srilanka
Children with persistent dipstick-positive proteinuria must undergo a quantitative measurement of protein excretion,
Result from
glomerular disease (most often minimal change disease)
nonpathologic conditions such as fever, intensive exercise, and orthostatic (or postural) proteinuria
