Proteinuria in Children

ALEXANDER K.C. LEUNG, MBBS, and ALEX H.C. WONG, MD

University of Calgary Faculty of Medicine, Calgary, Alberta, Canada

Proteinuria is common in children and may represent a benign condition or a serious underlying renal disease or systemic
disorder. Proteinuria may occur secondary to glomerular or tubular dysfunction. Although a 24-hour urine protein
excretion test is usually recommended, it may be impractical in children. A spot, first-morning urine test for
protein/creatinine ratio can be useful in this situation. Proteinuria is usually benign, in the form of transient or ortho-
static proteinuria. Persistent proteinuria may be associated with more serious renal diseases. Clinical features from the
history, physical examination, and laboratory tests help determine the cause of proteinuria. Treatment should be directed
at the underlying cause. Patients with active urinary sediments, persistent and gross hematuria, hyperten-sion,
hypocomplementemia, renal insufficiency with depressed glomerular filtration rate, or signs and symptoms suggestive of
vasculitic disease may require a renal biopsy and referral to a pediatric nephrologist. (Am Fam Physician.
2010;82(6):645-651. Copyright 2010 American Academy of Family Physicians.)
e for the primary care ter.1,9,10

T
The
physician is to electrostatic barrier
Patient information:
he presence separate benign consists of negatively
A handout on proteinuria is provided on page 652. protein of
in forms of pro-teinuria charged sialoproteins
from those with and pro-teoglycans.
urine
a is clinical significance. Most proteins, such as
common
laborator immuno-globulins G
y finding
in
Epidemiology
and M, are too large
children.
Although Proteinuria is (greater than 100 kDa)
proteinuri present at routine
a is to pass through the
usually urine test-ing in up
benign, glomerular barrier.
the to 10 percent of
condition Some have a charge or
can school-aged chil-
be a conforma-tion that
dren, although this prevents them from
marker
decreases to 0.1 traversing
for a
percent at repeated
serious
underlyi testing.4 A study
ng renal including mass
disease screening of school-
or aged children in
systemic Asia revealed
disorder. similar findings.5-7
1,2
When The prevalence
pro- increases with age,
teinuria peaks during
coexists adoles-cence, and is
with higher in girls.8
hematuri
a, the Mechanism of
likeli- Proteinuria
hood of The glomerular
clinicall barrier has three
y layers (the
significa fenestrated
nt renal endothelium, the
disease basement membrane,
is and the podocytes),
higher.2,3 forming both a size-
The selective and
challeng electrostatic fil-
 the filter. At least one half of the proteins in normal urine tubular permeability due to of normally filtered
are Tamm-Horsfall proteins, which are localized to the are the damage to the low-molecular-weight
thick ascending limbs of the loop of Henle. 11 The remain-pri-mary integrity of the proteins due to
ing proteins are filtered plasma proteins of different mechani glomerular filter.10 impaired reabsorp-tion
molecular sizes, including mostly low-molecular-weightsms in Proteinuria can also by the proximal
10,14
proteins (less than 40 kDa), such as transferrin, children. occur when a tubules. Secretory
10,12,14
microglobu-lins, and intermediate-sized albumin. 1,2,12,13 reduced number of proteinuria results
Most filtered proteins at the glomerulus are reabsorbed in Protein- functioning nephrons from oversecretion of
the proximal tubule. uria may leads to increased certain proteins in the
Slit diaphragms between podocytes have recently been result diffusion of pro-tein tubules, most notably
discovered. These slit dia-phragms contribute to thefrom across the remaining the oversecretion of
barrier effect. Mutations of the slit diaphragms can disrupt increase glomeruli. Tubular Tamm-Horsfall
normal function and lead to proteinuria.9 d proteinuria occurs proteins in interstitial
Mechanisms of proteinuria can be cat-egorized as glomerul when there is an nephritis. Overflow
glomerular, tubular, secretory, or overflow; glomerular and ar increased excretion proteinuria
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 Evidence
Clinical recommendations rating References

A 24-hour urine protein excretion test is often C 2, 18-19

difficult in children. Spot, first-morning urine
testing for UPr/Cr is more useful and correlates
well with the 24-hour urine collection. Spot, first-
morning urine testing should be used in children
if the urine dipstick test result is 1+ or more.
When a childs UPr/Cr is greater than 0.2 (greater C 2
than 0.5 for children six to 24 months of age)
or urinalysis results are abnormal, further
investigation with history, physical examination,
and blood work is recommended to rule out
significant renal disease.
Referral to a pediatric nephrologist should be C 2
considered if a definitive diagnosis is required or
a renal biopsy is considered.

UPr/Cr = urine protein/creatinine ratio.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to
http://www.aafp.org/afpsort.xml.

occurs when the plasma concentrations of low-molecular-weight proteins exceed the capacity of
the tubules to reabsorb the filtered protein. Examples include hemoglobinuria in intravascular
hemolysis and myoglobin-uria in rhabdomyolysis.

Measurement of Proteinuria
OFFICE TESTING
The urine dipstick test uses the tetrabro-mophenol blue colorimetric method, which is the most
widely used screening method. The intensity of color changes from yellow to blue and correlates
with the amount of protein in the urine: trace (10 mg per dL), 1+ (30 mg per dL), 2+ (100 mg per
dL), 3+ (300 mg per dL), and 4+ (1,000 mg per dL or greater). 15 A reading of 1+ or more is consid-
ered abnormal. The dipstick test primarily detects albuminuria, with a specificity and sensitivity of
more than 99 percent, 16 but is not sensitive for other proteins. The dip-stick test may yield false-
positive results for proteinuria with alkaline urine (pH greater than 8), concentrated urine (specific
gravity greater than 1.030), gross hematuria, pyuria, bacteriuria, prolonged immersion of reagent
strip in the urine, placement of reagent strip directly in the urine stream, and presence of
phenazopyridine or quaternary ammonium compounds in the urine. 12 False-negative results may
occur with acidic urine (pH less

than 4.5), dilute urine (specific gravity less than 1.010), and presence of proteins other than albumin in the urine. 12
The sulfosalicylic acid method, or turbi-dimetry, detects all forms of protein and is generally used as a
supplementary test when the presence of a low-molecular-weight or other protein is suspected but not detected by
the dipstick test. In the sulfosalicylic acid method, three drops of a sulfosalicylic acid 20% solution are added to 5
mL of urine. Depending on the amount of protein pre-cipitated, various grades of turbidity from minimal (trace) to
heavy flocculation (4+) are noted.2,3
QUANTITATIVE LABORATORY TESTING

The first-line test is 24-hour quantitative urine protein excretion. In children, the amount of urinary protein excretion
varies by age and body size. The normal amount is less than 4 mg per m 2 per hour or 100 mg per m 2 per day.2
However, this quantitative measurement is not practical in children, particularly if they are incontinent. 2 Also, it has
an inherent time delay, is often difficult to obtain in an outpatient setting, and is sub-ject to collection errors.
The single-void urine protein/creatinine ratio (UPr/Cr) calculated in milligrams of protein per milligrams of creatinine is
a convenient method for estimating urine protein excretion without a 24-hour urine collection. 2,17 Multiple studies have
found that the 24-hour urine protein test correlates well with UPr/Cr. 18-20 Multiplying UPr/Cr by 0.63 can give an estimate
of the total amount of protein (g per m2 per day) in the urine. Tubular secretion of creatinine increases in the presence of a
significant reduction in the glomerular filtration rate, and this might lead to an artificially low UPr/Cr. 18 Never-theless, the
UPr/Cr is useful for following trends in proteinuria. A spot, first-morning urine sampling is optimal for determining
UPr/Cr because it excludes any postural effect on the protein component.

Etiology
The etiology of proteinuria in children is diverse (Table 12,19,21,22), but a classification
www.aafp.org/afp Volume 82, Number 6 September 15, 2010
646 American Family Physician
Glomerular diseases are more common than tubulointerstitial
diseases.2,29,30 Albu-min and immunoglobulin G in the urine are the
usual indicators for glomerular diseases. Glomerular diseases can
have nephrotic and/ or nephritic features, and making a distinc-tion
scheme based on the clinical timing and fre- between these features can help nar-row the differential diagnosis.
quency of the problem can help narrow the Nephrotic
differential diagnosis. The orthostatic and
transient forms are benign and more com- September 15, 2010 Volume 82, Number 6
mon. Persistent proteinuria may be asso-
ciated with underlying renal diseases and
requires further investigation.
TRANSIENT PROTEINURIA

Transient (functional) proteinuria is tem-porary

and clears when the inciting factor remits or is
removed. Transient proteinuria can occur with
fever, exercise, stress, or cold exposure. 17,23,24 It
may also be caused by hemo-dynamic alterations
in glomerular blood flow.

ORTHOSTATIC PROTEINURIA

Orthostatic proteinuria is not uncom-mon in

children, particularly during ado-lescence.
The diagnosis is suggested with normal
protein excretion (i.e., negative dip-stick test
result or UPr/Cr of 0.2 or less) in a spot,
first-morning urine sample after the child
has been supine for the entire night, but
increased protein excretion (i.e., posi-tive
dipstick test result or UPr/Cr greater than
0.2) at least four to six hours after the child
has been upright.25 The cause of ortho-static
proteinuria is not clear; however, the
anatomic compression of the left renal vein
has been suggested.26 Long-term studies
with follow-up ranging from 20 to 50 years
have demonstrated a benign course.27,28
PERSISTENT PROTEINURIA

Persistent proteinuria can be glomeru-lar or

tubulointerstitial in origin. In both categories,
the causes can be primary, stem-ming
intrinsically from the renal tissue; or
secondary, mainly caused by systemic dis-
eases. When proteinuria is associated with
hematuria, renal dysfunction, and hyperten-
sion, significant renal disease may be present.2
 Table 1. Causes of Proteinuria in istent proteinuria
Children Glomerular
Adaptation (hyperfiltration) due to nephron loss (e.g., reflux
nephropathy secondary to vesicoureteric reflux)
Tr
Alport syndrome
a
Collagen vascular disease or vasculitis: Henoch-Schnlein purpura,
n
systemic lupus erythematosus
s
Diabetes mellitus
i
Glomerulopathy: minimal change glomerulopathy,* focal segmental
e glomerulosclerosis, mesangial proliferative glomerulonephritis,
n congenital nephrotic syndrome, immunoglobulin A nephropathy,
t membranoproliferative glomerulonephritis
( Infection: group A beta-hemolytic streptococcus infection, viral infection
f (hepatitis B, hepatitis C, human immunodeficiency virus, infectious
mononucleosis), other infection (malaria, syphilis)
u
Malignancies (lymphoma, solid
n
tumors) Toxin (mercury)
c
Tubulointerstitial
ti
Acute tubular necrosis: aminoglycosides, cisplatin, amphotericin B,
o
NSAIDs, radiocontrast media
n
Acute tubulointerstitial nephritis (NSAIDs, penicillin, cephalosporins,
a quinolones, sulfonamides, cimetidine [Tagamet], allopurinol [Zyloprim])
l Polycystic kidney disease
) Proximal renal tubular acidosis: Fanconi syndrome (global proximal tubule
p dysfunction), cystinosis, Lowe syndrome, galactosemia, Wilson disease
r Pyelonephritis
o Toxins (lead, copper, mercury)
t
e NSAID = nonsteroidal anti-inflammatory drug.
i *Most common form of nephrotic syndrome.
n Information from references 2, 19, 21, and 22.
u
r
i syndrome is characterized by heavy pro-
a
teinuria (greater than 1 g per m 2 per day or
UPr/Cr greater than 2.0), edema, hypoalbu-
I minemia (less than 25 g per L), and hyper-
d
lipidemia.18,30-32 Nephritic features include
i
hematuria; hypertension; oliguria; and active
o urinary sediments, such as red blood cells,
p white blood cells, and cellular casts.
a
Tubulointerstitial diseases are less com-
t
mon causes of proteinuria and usually
h
involve lowmolecular-weight proteins.
i
Proteinuria associated with renal tubular
c
disorders is generally mild. Tubular protein-
Related to medical condition (e.g., fever, seizure)
uria rarely presents a diagnostic dilemma
Unrelated to medical condition (e.g., exercise,
because the underlying disease is usually
stress, dehydration, cold exposure) Orthostatic
proteinuria
detected before the proteinuria.14,29
P Interstitial nephritis includes a vari-ety of
e pathologic processes involved in the
r
s www.aafp.org/afp American Family Physician 647
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atelev 22

i atio He
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Table 2. Clinical Clues to the Cause of Persistent Proteinuria in Children

Cause of proteinuria Clinical features Laboratory findings*

Glomerular
(hyperfiltration) due to Elevated serum
Adaptation History of vesicoureteric reflux or creatinine or
recurrent urinary
tract infection
blood urea
nephron loss
nitrogen level
amily purpu ent fever, butterfly rash, arthritis,
Alport syndrome Hearing history of ra hematuria, Positive
abnormality, decreased the
antinuclear antibody, pancytopenia,
vision, gross RBCs on
condition
areas erythematosus growth failure,
urinalysis Collagen vascular ;
h disease or multisystem involvement
arthrit
e vasculitis is; decreased complement C3
m Henoch- abdo and C4 levels
a Schnlein minal
t pain; Diabetes mellitus Polyuria,
u hema polydipsia, polyphagia, weight loss
r Nonblanchable, turia
i palpable purpura Elevated fasting blood
in gravity- System glucose and A1C levels,
a
ic lupus
, dependent glycosuria
WBCs, RBCs, Glomerulopathy
cellular casts on
f urinalysis Recurr
features,rec infe
Elevated alpha-fetoprotein laboratory
Congenital nephrotic ent ctio level in amniotic fluid, findings
Younger ns, nephrotic-range
upper respiratory Nephrotic-
than three months, tract infection, rheumatologic
proteinuria, disease, range
prematurity, low birth microscopic and malignancies
hypoalbuminemia,
hematuria
proteinuria,
syndrome hyperlipidemia hypoalbum
interspersedMesa
with
weight, episodes ofngialProteinuria of varying inemia,
placentomegaly, macroscopic prolif degrees, including hyperlipide
edema at birth or hematuria erativ nephrotic-range proteinuria; mia,
during Membranopr hypoalbuminemia; thrombocyt
oliferative
first e
hyperlipidemia; osis,
week Neph
thrombocytosis; normal normal
of life rotic
Nephrotic featu complement levels; HIV compleme
Focal segmental and/or
res, serology nt levels
Nephrotic nephritic hem Hematuria, elevated serum
features;
or nephritic aturi IgA, normal complement
history of
features,history of a C3 and C4 levels
chronic
HIV
glomerulo glo
glomerulosclerosis me Hematuria, decreased
nephritis
rulo complement C3 level,
nep
usually normal
IgA nephropathy hepatitis hriti
B or C; complement C4 level,
s
Usually may be positive hepatitis
older than 10 years, associate serology results,
nephritic d with possibly nephrotic
Minimal youn n Nephroti s, nt levels levels;
ccal Recent
ger P c-range n dysmo
change Most than pharyngitis or skin
o protein or rphic
common form of six infection, nephritic Positive throat
s uria, m RBCs
nephrotic year features swab
t hypoal al or
syndrome, facial s, s results;
glomerulonephriti bumine c
or RBC
may tr s elevated
glomerulopat be mia, o casts
e antistreptoly
hy p hyperli m on
associated with sin O titer;
t
recent viral infection pidemi pl urinaly
decreased
generalized or allergy o a, e sis
complement
edema, c thromb m
Infectio C3 and C4
o ocytosi e
Malignancies depen n ficiency virus; IGA laborator cou electrolyt tests for specific
d on i = immunoglobulin y work- nt e, blood liste conditions.
the m A; NSAID = up for and urea d in Distinguishing
Weight loss, underlying m nonsteroidal anti- suspecte
cause me nitro-gen, this among the different
cachexia u inflammatory drug; d renal asu and tabl types of
conti
disease rem serum e glomerulopathy is
nued n RBC = red blood
includes ent creatinine can difficult clinically;
Abnormal o cell; WBC = white a of levels. help therefore, they are
laboratory HIV = d blood cell. complet ser Additional eval generally
findings e e blood um laboratory uate diagnosed
huma *Basic
histologically. protei h albuminemia, and hyperten and urinary cause in
Nephrotic nuria, y hyperlipidemia; sion, acti sediment Also glomerular
a proteinuria.
features: edem p nephritic features: oliguria, ve s. rare
heavy a, o hematuria,
dire satients with(2 mg m2 div weeks, ther into
cte eidiopathic per pe ide followed byapy lera
d at . nephrotic kg r maxim d treatment onfails ble,
The the 2syndrome per da um of dos alternate daysor seco
treatment und , should day, y 80 mg es for anotheradv nd-
of erly 2receive a trialor 60 to per for four to sixerse line
persistent ing
9of mg a day) in fou weeks.35 Ifeffe ther
proteinuria cau prednisone per up to r tosteroid cts apy
should be P three six are
r ,2010 Num w w.aaf af American Ph cia 649
Septembe 15 Volume 82, ber 6 w p.org/ p Family ysi n
Table 2. Clinical Clues to the Cause of Persistent Proteinuria in Children (continued)

Cause of proteinuria Clinical features Laboratory findings*

Tubulointerstitial
fever, rash Elevated serum
Acute tubular necrosis Medication creatinine or blood
history: aminoglycosides, cisplatin, urea nitrogen
amphotericin B, levels; granular
NSAIDs; history casts, epithelial cell
of radiocontrast
casts, renal tubular
media
epithelial cell casts
Acute tubulointerstitial Medication on urinalysis
history: NSAIDs, penicillin, cephalosporins, Acute rise in serum
nephritis quinolones, sulfonamides, cimetidine creatinine level,
(Tagamet), eosinophilia,
allopurinol (Zyloprim); nonspecific malaise, WBC casts on
urinalysis
renal tests listed in this table can help evaluate
Polycystic kidney disease Hematuria, hypertension, renal insufficiency,
disease for specific conditions.
nephromegaly, family historyincludes
of the condition
a Distinguishing among the different
Proximal renal tubular Cystinosis: visual impairment, Fanconi
completesyndrome,
types of thyroid
glomerulopathy is difficult
acidosis blood
disorder, hepatosplenomegaly, count clinically;
delayed puberty therefore, they are generally
HIV = human and diagnosed histologically.
Fanconi syndrome: growth failure, polyuria,
measurem
polydipsia
immunodeficiency Nephrotic features: heavy proteinuria,
Lowe syndrome:
virus; IGA = cataracts, Fanconi
ent of syndrome, hypotonia
edema, hypoalbuminemia, and
Wilson disease: Kayser-Fleischer serum rings on slit lamp
immunoglobulin A;
electrolyte, hyperlipidemia; nephritic features:
examination, liver dysfunction or cirrhosis
NSAID = nonsteroidal blood urea hematuria, hypertension, oliguria, and
Pyelonephritis anti-inflammatory
Fever, chills, flank and costovertebral
nitro-gen,tenderness,
drug; RBC =irritative
red blood active urinary sediments.
hematuria, and serum
urinary symptoms
cell; WBC = white creatinine Also a rare cause in glomerular
Toxins Copper: history of exposure (e.g., food containers)
blood cell. proteinuria.
levels.
Lead: history of exposure, constipation,
Additional lead line along
Information from references 2, 19, 21,
*Basic laboratory
gum margin, cognitive or laboratoryimpairment
behavioral and 22.
work-up for suspected
Kidney from a
renal biopsy.2 Alberta,
Canad Int pediatri
EDITORS NOTE:
a, andALEX H.C. WONG, MD, is a Suppl. c
This article is is aclinical lecturer in the Depart- 2004; nephrol
(e.g., based on content (92):S7 ogy
pediatri ment of Family Medicine at
cyclophosphamide, that Dr. Leung is c the University of Calgary
6-S89. panel
establis
chlorambucil [Leu-preparing for a consult Faculty of Medicine. He is a
2. hed at
keran], cyclosporinechapter in a book ant atfamily physician and sports
Hogg RJ, the
[Sandimmune]) maytitled Common the medicine consultant in Nationa
Portma
Prob-lems in Alberta Calgary, Alberta.
be required.36 InAmbulatory Childre
n RJ, l
Milliner Kidney
patients with renalPediatrics. The ns Address correspondence to D, Founda
dysfunc-tion, anbook will be Hospita Alexander K.C. Leung, Lemley tion
adjunctive published by l. MBBS, Alberta Childrens KV, confere
Hospital/University of Eddy A, nce on
angiotensin- Nova Science
Calgary, #200, 233 16th protein-
Ingelfin
converting enzymePublishers, Inc., Ave. NW, Calgary, Alberta, ger J. uria,
Hauppauge, NY.
inhibitor and/or Canada, T2M OH5 (e-mail: Evaluat albumin
aleung@ucalgary.ca). ion and uria,
angiotensin-II
Reprints are not available manag risk,
receptor blocker canThe ement assess
from the authors.
be used to decreaseAuthors of ment,
pro-teinuria andALEXANDER Author disclosure: Nothing protein- detectio
to disclose. uria n, and
slow progression ofK.C. LEUNG, elim-
and
renal dis-ease.37-40MBBS, is a nephrot ination
Referral to aclinical REFERENCES ic (PARA
professor of syndro DE).
pediatric pediatrics at Pediatri
nephrologist may bethe University 1. Zandi-Nejad K, Eddy
me in
children cs.
needed for aof Calgary AA, Glassock RJ, Brenner : 2000;1
BM. Why is proteinuria an 05(6):1
definitive diagnosisFaculty of
ominous biomarker of
recom
Medicine in menda- 242-
or consideration of progressive kid-ney disease? tions 1249.

Family .aafp.org/afp Numbe Septem 2010

650 American Physician www Volume 82, r 6 ber 15,
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