clinical approach to pediatric proteinuria

Clinical Approach to
Pediatric
Proteinuria
Dr. Simin Sadeghi
E-Mail: sisadegh@yahoo.com
1

Epidemiology
• The prevalence of proteinuria on a random urine specimen in otherwise asymptomatic
school-aged children and adolescents is approximately 5% to 15% based on multiple
largescale studies
• This finding decreases substantially with repeated urine samples
• One study examined 4 repeated urine specimens from each of approximately 9,000
children (8–15 years old); 1 of 4 specimens was positive for protein in 10.7% of patients,
but only 0.1% had 4 of 4 specimens positive with persistent proteinuria
• The prevalence increases with increasing age and peaks in adolescence. One study
reported that the peak prevalence in females is 13 years of age and in boys is 16 years of
age
2

Definitions
• Proteinuria is defined as protein excretion greater than 100 mg/m2 per day
or more than 0.2 mg protein/mg creatinine (also known as a urine
protein/creatinine ratio ([U p/c] >0.2) on a single spot urine collection
• in neonates and infants: a higher amount of protein excretion, up to 300
mg/m2
• Nephrotic-range proteinuria is defined as greater than 1,000 mg/m2 per day
or greater than 50 mg/kg per day, or a U p/c greater than 2 on a single spot
urine collection
4

Measurement Methods
Proteinuria can be evaluated using the following methods:
• Urinary dipstick reagent
• SulfoSalicylic Acid (SSA) turbidity tests
• Random or first morning urine (FMU) for spot urine protein-to-
creatinine ratio (UPCR)
• The 24 hours urinary protein and creatinine, urine protein
electrophoresis , urinary micro albumin
5

The urinary dipstick reagent test
• is routinely used in clinical practice
• It is highly sensitive solely for the measurement of albumin
concentration via colorimetric reactions
• Its main limitation is that it cannot detect other types of
proteins such as plasma proteins, globulins, and low-
molecular-weight proteins
6

The urinary dipstick reagent test
The graded scale is stated as follows:
• negative (less than 10 mg/dL)
• trace (10-29 mg/dL)
• 1+ (30-100 mg/dL)
• 2+ (100-300 mg/dL)
• 3+ (300-1,000 mg/dL)
• 4+ (>1,000 mg/dL)5)
• The dipstick largely detects albumin and does not tend to detect LMW proteins.
8

False-positive urine dipstick for protein :
• High specific gravity (ie, a concentrated urine)
• Very alkaline
• Macroscopic hematuria, pyuria
• Contamination with antiseptic agents or iodinated radiocontrast agents
False-negative results :
• in patients with very dilute urine specimens
• in disease states where albumin is not the predominant urinary protein
9

The qualitative SSA turbidity test
• Is not routinely used in clinical practice for assessment of
proteinuria
• It has the potential to detect a broad range of urinary proteins
including albumin, immunoglobulins, and Bence-Jones
• This turbidometric method of testing is useful in the diagnosis
of multiple myeloma, characterized by the excretion of light-
chain Ig
• The SSA reagent is added to a fresh urine specimen, and the
degree of turbidity is correlated with the amount of proteinuria
based on a predetermined scale
10

The qualitative SSA turbidity test
False positive :
• recent exposure to radiographic contrast material,
high concentrations of penicillin or cephalosporin
antibiotics, or with high uric acid concentration in the
urine
False negative :
• highly buffered alkaline or diluted urine specimens
11

Random or first morning urine (FMU)
Calculation of a urine protein-to-creatinine ratio in a random or spot
urine sample especially when tested in the first morning urine
specimen
• Ratio higher than 0.8-1.0 are generally considered abnormal in infants
less than 6 months of age
• Ratio less than 0.5 are considered normal for children 6-24 months of
age,
• less than 0.2 for children older than 24 months of age and adult
12

Random or first morning urine (FMU)
Falsely elevated Urine p/c when there is not enough creatinine
excreted :
• children with low muscle mass or severe malnutrition, due to the
low rate of creatinine excretion
• underestimation of the ratio when there is a very concentrated
sample with a high creatinine level in the urine
13

The 24 hours urinary protein
The 24 hours urine specimen collection is still the gold standard for quantitative
urinalysis. Variations in quantification can be reduced using the body surface area.
This results in the followings:
• normal, ≤4 mg/m2 /hour
• proteinuria, 4-40 mg/m2 /hour
• nephrotic-range proteinuria, >40 mg/m2 /hour
A more accurate method 24-hour urine collection
Adequacy of a 24-hour urine collection may be verified by measurement of urine
creatinine, which is approximately 15 to 20 mg/kg ideal body weight in females and 20
to 25 mg/kg body weight in males.
14

Urine protein electrophoresis
• Evaluated on a urine bag specimen in infants or from a
clean catch urine collection in older children and
adolescents
• This testing will elucidate the percent of proteinuria
content, that is, albumin, beta2-microglobulin, alpha
globulins, monoclonal proteins, etc
• If a malignancy involving the over-production of
immunoglobulins is suspected, a urine immunofixation
electrophoresis can also be assessed.
15

Urine microalbumin level :
• urine microalbumin to creatinine ratio (MA:Cr) can be calculated, similar to
a urine protein-to creatinine ratio
• The normal range is less than 20–30 mg of urine albumin per gram of
creatinine on a first morning specimen
• Microalbuminuria as a urine albumin excretion level of 20–200 mg/min/
1.73 m2 or 30–300 mg albumin per gram creatinine per 24 h and frank
proteinuria as greater than 200 mg/min/ 1.73 m2
• This ratio should be assessed on a first morning urine specimen. In patients
with type I and type II diabetes mellitus, microalbuminuria has been shown
in numerous studies to be a predictor of progressive renal disease and
potentially cardiovascular morbidity and mortality
16

Classification 17
Classification
Transient
Orthostatic Persistent

Transient Proteinuria
• Proteinuria noted on 1 or 2 occasions but not present on subsequent
testing, is often seen in the context of fever, exercise, stress, seizures,
and hypovolemic/ dehydration status , cold exposure.
• It is temporary and disappears when the inciting factor is resolved
• Transient proteinuria may not be associated with any significant renal
disease.
• Proteinuria does not exceed 1+ to 2+ in this case using the urine dipstick
method.
• Caused by hemodynamic changes in the glomerular blood flow Although
these changes result in increased protein diffusion, further evaluation or
treatment for these children is unnecessary.
18

Orthostatic Proteinuria
• Characterized by increased protein excretion in the upright position,
which returns to normal when the patient is recumbent
• Orthostatic or postural proteinuria is more common in older children and
adolescents, accounting for approximately 5% of proteinuria
• This type of proteinuria is usually asymptomatic and can easily be detected
using urinary screening tests
• This condition has the hallmark of increased protein excretion in the
upright position.
19

20
• Urinary dipstick testing via first morning urine
collection, (UPr/UCr), and 24-h urine
collections can all be used for diagnosis, but
24-h collections are rarely required if the FMU
is collected appropriately
• The collection of FMU is critical for its
diagnosis. The patients must fully void
themselves of urine before going to bed and
collect the FMU immediately after waking up

22
• On average, these patients excrete less than 1 g of protein in 24
hours in the upright position, and this normalizes to less than 50
mg in 8 hours of supine position
• In this type of proteinuria, the total urinary protein excretion may
be increased up to 1 g/day, but it rarely exceeds this level
• It is diagnosed when a first morning urine sample is less than 0.2
mg protein/mg creatinine in the setting of a U p/c greater than
0.2, or positive urine dipstick for proteinuria, in a random urine
sample

23
• Other symptoms (hematuria, edema, hypertension,
and renal dysfunction) must be absent.
• The exact etiology of orthostatic proteinuria is still
unclear
• Multiple factors:
• renal hemodynamic changes
• partial left renal vein compression
• increased permeability of the capillary walls
• circulating immune complexes

24
• Most of the studies are not on pediatric cases, and late-onset
glomerulosclerosis have been reported. Therefore, periodic
monitoring of the spot FMU test and blood pressure have been
recommended
• Studies from the 1960s to the 1990s on up to 40 to 50 years after
the diagnosis of orthostatic proteinuria have reported a benign
course for this condition, where mortality is not shown to be
greater than the average healthy population with similar
demographic characteristics in the absence of other clinical
evidence of renal disease.

Fixed Proteinuria
• Is defined as FMU that shows ≥1+ on dipstick reagent test with
UPCR of ≥0.2 or with a urine specific gravity >1.015
• Fixed proteinuria may be indicative of underlying renal
pathology. Therefore, if fixed proteinuria on FMU is found after
three or more urinalysis performed every few weeks, these
patients required close follow-up and should be further
evaluated
• Persistent proteinuria may be subclassified as glomerular,
tubular, or overflow
25

Overflow Proteinuria
• Increased excretion of LMW proteins that results from
marked overproduction of LMW proteins, leading to a level
that exceeds tubular reabsorptive capacity
• Multiple myeloma is the most common cause of overflow
proteinuria. Another example of overflow proteinuria is
found in pediatric patients with myoglobinuria.
26

Tubular Proteinuria
• Increased excretion of proteins due to interference with
proximal tubular reabsorption
• most often appears as a result of injury to the proximal tubule
and in the pediatric population is more commonly secondary
rather than primary in nature
• Tubular damage, often induced by various drug exposures or
circulatory compromise, results in impaired ability to reabsorb
the LMW proteins, which are normally filtered by the glomerulus
and reabsorbed by the proximal tubule
27

• The amount of tubular proteins excreted in tubular diseases is
generally smaller than that in glomerular proteinuria, which is
less than 2 g/day
• Dent’s disease is an X-linked recessive disorder of the
proximal tubules characterized by hypercalciuria, low-
molecular weight proteinuria, and nephrolithiasis. Most of the
cases of Dent’s disease have mutations that inactivate the
voltagegated chloride transporter named CLC-5.
• Patients with Lowe syndrome (also called the
oculocerebrorenal syndrome of Lowe), generally have
proximal tubulopathy, bilateral cataracts, and hypotonia
28

29
• Secondary rather than primary causes of tubular
proteinuria are more likely to be encountered in
children (such as acute tubular necrosis and
acute interstitial nephritis)
• One should take note of a few primary causes
that may be considered, including but not limited
to cystinosis, polycystic kidney disease, Wilson
disease, and mitochondrial disorders and sickle
cell disease nephropathy

Glomerular Proteinuria
• Minimal change disease also called lipoid nephrotic syndrome can be
mostly seen in selective proteinuria pediatric patients
• Most forms of glomerulonephritis are followed by nonselective
proteinuria
• This degree of selectivity can be determined by measuring albumin and
other proteins of higher molecular weights such as transferrin or IgG
• Highly selective proteinuria may have an IgG: albumin ratio of can play
an important role in their progression
30

Glomerular Proteinuria
• The abnormally high passage of proteins across the glomerular
capillary wall and mesangium may aggravate glomerular injury
• Persistent proteinuria often indicates underlying renal pathology
• Glomerular causes for proteinuria are more common than
tubulointerstitial causes of proteinuria
31

Among the most common causes of primary glomerular
proteinuria:
• Minimal change disease (MCD) represents one of the most
common presentations of idiopathic nephrotic syndrome. It
classically presents in children (most between 3 and 9 years of age)
as edema, a low albumin level (25% of birthweight)
• Acute postinfectious GN and HSP are known to be secondary
causes of glomerular proteinuria
• Lupus nephritis, which is the term used to describe the renal
(usually glomerular) involvement of systemic lupus erythematosus
(SLE)
• Renal disease is present in 50% to 75% of children with SLE and is
one of the leading causes of morbidity and mortality
32

• Note that persistent proteinuria is associated with CKD
• Proteinuria that is persistent may be the first sign of glomerular
damage or loss of renal function
• It has long been established that the degree of proteinuria is
associated with progression of CKD
• Not only does protein serve as an indicator of renal damage, but
it is also recognized as a perpetrator of ongoing renal damage
• As such, children who present with persistent proteinuria should
undergo evaluation of renal function, and a thorough history
detailing any significant illnesses or prenatal or perinatal events is
essential to help determine possible causes
33

Isolated proteinuria
• Asymptomatic proteinuria in an otherwise healthy patient with normal
physical exam findings, blood pressure readings, urinary sediment, and
laboratory findings at the time of diagnosis. Usually the degree of
proteinuria is less than 2 g in 24 h
• The majority of these individuals do not have progressive renal disease,
although in some studies, a minority of renal biopsy specimens revealed
abnormal histology such as focal segmental glomerulosclerosis
• Some studies predict a 20% risk for progressive renal damage over a 10-
year period. Therefore, an initial thorough evaluation as well as close
long-term monitoring is indicated, and a referral to a pediatric
nephrologist is recommended.
34

Persistent asymptomatic proteinuria
• This is the type of proteinuria not associated with hematuria but
proteinuria persists on FMU for more than 3 months
• The prevalence of persistent proteinuria in children may be as high as 6%
• This type is not associated with edema and the average amount of
proteins excreted is approximately<2 gr/day
• Causes of persistent asymptomatic proteinuria include membranous and
membranoproliferative glomerulonephritis, pyelonephritis,
developmental anomalies, hereditary nephritis, hepatitis B infection,
and “benign” proteinuria
35

Persistent asymptomatic proteinuria
• The evaluation should start with thorough history and physical
examination
• If the results of the laboratory tests are within normal range with
the indication of low grade proteinuria (150-1,000 mg/day), renal
biopsy is not recommended, as it is rare to find evidence for
progressive renal disease
• These patients should be subjected to annual evaluation including
physical examinations, routine blood pressure monitoring, and
laboratory tests like urinalysis, 24 hours urine specimen collection,
and creatinine clearance
36

Evaluation of Proteinuria
History:
• Symptoms of hypertension, oliguria, polyuria, weight loss, skin lesions,
joint symptoms, recent infections, previous abnormal urinalyses, and
recent intake of medications (such as NSAIDs, gold, angiotensin converting
enzyme inhibitors (ACEi), and penicillamine)
• Family history of hypertension, renal disease, autoimmune disease, and
visual impairment or deafness should also be considered
• Growth is an important clue for chronic diseases such as renal disease and
needs to be measured
• Blood pressure also needs to be routinely measured
• Signs of edema, flank pain, fluid overload, organomegaly, rashes, anemia,
joint swelling, and symptoms of osteodystrophy should be examined.
37

• The first step is to confirm that the children have fixed proteinuria on
FMU
• Patients with a positive urine dipstick (1+) of protein should have a
complete UA and quantification of proteinuria with a spot U p/c,
preferably in a first morning urine sample
• This sample is best obtained by completely emptying the bladder
before going to sleep (discarding that urine) and collecting the urine
on awakening, before any other activity is performed
• No further evaluation is necessary if the first morning urine sample
has a normal U p/c of 0.2 or less because the most likely diagnosis is
orthostatic proteinuria and historically is not associated with long-
term sequelae
• Still, some pediatric nephrologists would advise repeating a first
morning void on a yearly basis in patients who continue to
demonstrate proteinuria
39

• If the children have fixed
proteinuria on FMU on
three separate occasions, U
p/c is greater than 0.2 the
following evaluation is
required
40
• A complete urinalysis evaluation of
the children with fixed proteinuria is
required to determine the absence
or presence of hematuria with
dysmorphic or eumorphic red blood
cells, pyuria, urine eosinophils, or
crystals.

Step 2:
Laboratory tests, such as electrolyte balance, renal function test,
complete blood count, tests for serum albumin, and complement 3 or 4
(C3 or C4) activity levels should also be examined. The anti-streptolysin
O titers, antinuclear antibody levels, and DNase B titers may also be
considered in certain situations, 24 hours urine specimen collection may
be necessary for this step
• Chest x-ray and kidney ultrasound imaging should be performed to
determine volume overload or renal structural abnormalities
• Further studies may include hepatitis B and C tests, more specific
laboratory studies on vasculitis or autoimmune diseases as well as the
type of proteinuria
41

Possible Indications for Percutaneous Renal
Biopsy in Patients with Persistent Proteinuria
• Elevated serum creatinine concentration
• Persistent macroscopic or microscopic hematuria or heavy
proteinuria (>1 g/day)
• Hypertension
• Persistent hypocomplementemia
• Consider with frequently relapsing, steroid-dependent and steroid-
resistant nephrotic syndrome
• Family history of chronic renal disease or end-stage renal disease
• Parental anxiety
42

Take Home Massage
• Transient and orthostatic proteinuria renders an excellent long-term
prognosis
• while isolated and persistent proteinuria often portends poorer
long-term outcomes
• Initial evaluation and continued long-term monitoring of these
patients can significantly alter potential progression of the
underlying process
• Family and age-appropriate patient education and counseling should
be performed at or soon after the diagnosis of significant proteinuria
is confirmed and then continued over time by a multidisciplinary
team
44

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