Introduction to a child with proteinuria

Introduction to theIntroduction to the
Child with ProteinuriaChild with Proteinuria
Prof. Dr.Prof. Dr.
Saad S Al AniSaad S Al Ani
Senior PediatricSenior Pediatric
consultantconsultant
Head of PediatricHead of Pediatric
DepartmentDepartment
KhorfakkanKhorfakkan
hospitalhospital
Sharjah ,UAESharjah ,UAE
saadsalani@yahoo.com

IntroductionIntroduction
""The demonstration of proteinuria on a routineThe demonstration of proteinuria on a routine
screening urinalysis isscreening urinalysis is commoncommon ""
"" Protein can be found in the urine of healthyProtein can be found in the urine of healthy
children , with a reasonablechildren , with a reasonable upper limitupper limit beingbeing
150mg/24hr150mg/24hr ((4 mg/m2/hr4 mg/m2/hr)) ""
1. http://www.aafp.org/afp/2010/0915/p645.html
2. http://emedicine.medscape.com/article/984289-overview

Cont.Cont.
""10%10% of children aged 8-15 yr testof children aged 8-15 yr test positivepositive forfor
proteinuria byproteinuria by urinary dipstickurinary dipstick at some timeat some time ""
"" In a 24-hour urine collection:In a 24-hour urine collection:
NormalNormal values :values : <4 mg of protein/m2/hr<4 mg of protein/m2/hr
SignificantSignificant values :values : 4–40 mg/m2/hr4–40 mg/m2/hr
NephroticNephrotic range:range: >40 mg/m2/hr>40 mg/m2/hr ""
http://brightfutures.aap.org/3rd_edition_guidelines_and_pocket_

Cont.Cont.
"" Assess completeness of 24-hour collectionAssess completeness of 24-hour collection
by simultaneously measuringby simultaneously measuring urineurine
creatininecreatinine :: ≥15 mg/kg body weight≥15 mg/kg body weight inin
aa 24-hour collection24-hour collection""
"" The challenge is to differentiate the childThe challenge is to differentiate the child
withwith proteinuria related to renal diseaseproteinuria related to renal disease fromfrom
the otherwisethe otherwise healthy child with transienthealthy child with transient oror
otherother benign forms of proteinuriabenign forms of proteinuria
""

Urinary dipstick testUrinary dipstick test
"" DipsticksDipsticks primarily detectprimarily detect albuminuriaalbuminuria
and areand are less sensitive for otherless sensitive for other forms offorms of
proteinuria:proteinuria:
- low molecular weight proteins- low molecular weight proteins
- Bence Jones protein- Bence Jones protein
- gamma globulins- gamma globulins ""
"" TheThe urinary dipstick testurinary dipstick test offers a qualitativeoffers a qualitative
assessment of urinary protein excretionassessment of urinary protein excretion""
http://www.fpnotebook.com/Urology/Peds/PrtnrInChldrn.htm

The dipstick is reported asThe dipstick is reported as::
NegativeNegative 22+ : (+ : (100100mg/dlmg/dl))
Trace :(10 – 20 mg/dlTrace :(10 – 20 mg/dl)) 33+ : (+ : (300300mg/dlmg/dl))
11+ : (+ : (3030mg/dlmg/dl)) 44+: (+: (10001000--20002000mg/dlmg/dl))
Cont.Cont.
http://www.hopkinschildrens.org/proteinuria.aspx

Cont.Cont.
"" False-negative testFalse-negative test results can occur with:results can occur with:
1. Dilute urine (specific gravity <1.005)1. Dilute urine (specific gravity <1.005)
2. Disease states in which the predominant2. Disease states in which the predominant
urinary protein is not albuminurinary protein is not albumin""

Cont.Cont.
"" False-positive testFalse-positive test results may be seen withresults may be seen with
11.Gross hematuria.Gross hematuria
2. Contamination with2. Contamination with antiseptic agentsantiseptic agents
i. Chlorhexidinei. Chlorhexidine
ii. Benzalkonium chlorideii. Benzalkonium chloride
iii. Hydrogen peroxideiii. Hydrogen peroxide
33.Urinary pH >7.0.Urinary pH >7.0
44.Phenazopyridine therapy.Phenazopyridine therapy""

"" Because the dipstick reactionBecause the dipstick reaction offers onlyoffers only
a qualitative measurementa qualitative measurement of urinaryof urinary
protein excretion, children withprotein excretion, children with
persistent proteinuriapersistent proteinuria should haveshould have
proteinuria quantitatedproteinuria quantitated with the morewith the more
preciseprecise spot urine protein: creatininespot urine protein: creatinine
ratio (UPr : UCr)ratio (UPr : UCr) ""
Cont.Cont.

"" ThisThis ratioratio isis calculated by dividingcalculated by dividing thethe
UPr (mg/dL) concentration by the UCrUPr (mg/dL) concentration by the UCr
(mg/dL) concentration(mg/dL) concentration and is bestand is best
performed on aperformed on a first morning voided urinefirst morning voided urine
specimenspecimen to eliminate the possibility ofto eliminate the possibility of
orthostatic (postural) proteinuriaorthostatic (postural) proteinuria ""
Cont.Cont.

"" Ratios :Ratios :
<0.5<0.5 in children <2 yr of agein children <2 yr of age
<0.2<0.2 in children ≥2 yr of agein children ≥2 yr of age
suggestsuggest normal protein excretion.normal protein excretion. ""
Cont.Cont.
"" A ratioA ratio >2>2 suggestssuggests nephrotic-range proteinuria.nephrotic-range proteinuria. ""
"" UPr : UCr ratiosUPr : UCr ratios have been shownhave been shown
to have ato have a high correlation withhigh correlation with
protein excretion determinationsprotein excretion determinations inin
timed urine collectiontimed urine collection ""

"" DefinedDefined as the presence of albumin in theas the presence of albumin in the
urine above the normal level but belowurine above the normal level but below
the detectable range of conventional urinethe detectable range of conventional urine
dipstick methodsdipstick methods ""
MicroalbuminuriaMicroalbuminuria
"" TheThe mean level of albumin excretionmean level of albumin excretion hashas
been shown fall betweenbeen shown fall between 8 and 10 mg/g8 and 10 mg/g
creatininecreatinine in childrenin children >6 yr old>6 yr old ""

Cont.Cont.
"" Microalbuminuria in children has beenMicroalbuminuria in children has been
found to befound to be associated with obesityassociated with obesity andand
toto predictpredict, with reasonable specificity,, with reasonable specificity,
thethe development of diabetic nephropathydevelopment of diabetic nephropathy
inin type 1 diabetes mellitustype 1 diabetes mellitus ""

Causes of proteinuriaCauses of proteinuria

"" The majority of children found to haveThe majority of children found to have
positive urinary dipstick values for proteinpositive urinary dipstick values for protein
havehave normal dipstick values on repeatednormal dipstick values on repeated
measurementsmeasurements ""
1.Transient Proteinuria1.Transient Proteinuria
"" ApproximatelyApproximately 10%10% of children whoof children who
undergoundergo random urinalysisrandom urinalysis havehave proteinuriaproteinuria
by a single dipstick measurementby a single dipstick measurement.. ""

1.Transient Proteinuria(cont.)1.Transient Proteinuria(cont.)
"" Across the school-age spectrum thisAcross the school-age spectrum this
finding occurs morefinding occurs more commonly incommonly in
adolescentsadolescents than in younger childrenthan in younger children ""
"" In mostIn most cases, serial testing of thecases, serial testing of the
patient’s urine demonstratespatient’s urine demonstrates resolutionresolution
of the abnormality.of the abnormality. ""
http://emedicine.medscape.com/article/984289-overv

1.Transient Proteinuria(cont.)1.Transient Proteinuria(cont.)
"" The proteinuria usuallyThe proteinuria usually doesdoes
not exceed 1-2+ on the dipsticknot exceed 1-2+ on the dipstick ""
"" ItsIts causecause remainsremains elusiveelusive ""
Defined contributing factors include :
Temperature >38.3°C (101°F)
Exercise Heart failure
Dehydration Seizures
Cold exposure Stress
"" No evaluation or therapyNo evaluation or therapy is neededis needed ""

"" Orthostatic proteinuria is theOrthostatic proteinuria is the mostmost
common cause of persistent proteinuriacommon cause of persistent proteinuria inin
school-aged childrenschool-aged children andand adolescentsadolescents ""
2.Orthostatic (Postural) Proteinuria2.Orthostatic (Postural) Proteinuria
"" Occurring in up toOccurring in up to 60%60% of children withof children with
persistent proteinuriapersistent proteinuria ""
http://emedicine.medscape.com/article/984289-overview#

2.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)
"" Patients with orthostatic proteinuriaPatients with orthostatic proteinuria
excrete normal or minimally increasedexcrete normal or minimally increased
amountsamounts of protein in theof protein in the supine positionsupine position.. ""
"" Children with this condition areChildren with this condition are usuallyusually
asymptomaticasymptomatic, and the condition is, and the condition is discovereddiscovered
on routine urinalysison routine urinalysis.. ""

"" In theIn the upright positionupright position, urinary protein, urinary protein
excretion may beexcretion may be increased 10-foldincreased 10-fold, up, up
to 1,000 mg/24 hr (1 g/24 hr).to 1,000 mg/24 hr (1 g/24 hr). ""
""Hematuria, hypertension, hypoalbuminemia,Hematuria, hypertension, hypoalbuminemia,
edema, and renal dysfunctionedema, and renal dysfunction are absentare absent.. ""

"" The initial evaluation should include anThe initial evaluation should include an
assessment for orthostatic proteinuriaassessment for orthostatic proteinuria, a, a
condition in which thecondition in which the 24-hr urinary protein24-hr urinary protein
excretion rarely exceeds 1 gexcretion rarely exceeds 1 g ""

"" It begins with the collection of aIt begins with the collection of a firstfirst
morning urine samplemorning urine sample, with subsequent, with subsequent
testing of any urinary abnormalities by atesting of any urinary abnormalities by a
complete urinalysiscomplete urinalysis andand determination of adetermination of a
spot protein : creatinine (Pr : Cr) ratiospot protein : creatinine (Pr : Cr) ratio. ""

"" TheThe absence of proteinuriaabsence of proteinuria (dipstick(dipstick
negative or trace for protein and urine Pr :negative or trace for protein and urine Pr :
Cr ratio <0.2) in the first morning urineCr ratio <0.2) in the first morning urine
sample forsample for 3 consecutive days confirms3 consecutive days confirms thethe
diagnosis of orthostatic proteinuriadiagnosis of orthostatic proteinuria ""
"" TheThe correct collectioncorrect collection of theof the first morningfirst morning
urineurine sample issample is criticalcritical.. ""

"" TheThe causecause of orthostatic proteinuria isof orthostatic proteinuria is
unknownunknown, although, although
i. Altered renal hemodynamicsi. Altered renal hemodynamics
ii. Partial renal vein obstruction inii. Partial renal vein obstruction in
the upright position arethe upright position are possiblepossible
causescauses.. ""
"" NoNo further evaluation is necessary, and thefurther evaluation is necessary, and the
patient and family should bepatient and family should be reassuredreassured ofof
thethe benign naturebenign nature of this condition.of this condition. ""

3.Fixed Proteinuria3.Fixed Proteinuria
"" Fixed proteinuriaFixed proteinuria indicates renal diseaseindicates renal disease
and may be caused by either :and may be caused by either :
glomerularglomerular oror tubular disorderstubular disorders ""
"" Persons found to have:Persons found to have:
Significant proteinuriaSignificant proteinuria on aon a first morningfirst morning
urine sampleurine sample onon 3 consecutive days3 consecutive days (>1+(>1+
on dipstick ,urine specific gravity >1.015on dipstick ,urine specific gravity >1.015
or protein : creatinine ratio >0.2)or protein : creatinine ratio >0.2) ""

Initial evaluationInitial evaluation
"" Initial evaluation of a child with fixedInitial evaluation of a child with fixed
proteinuria should include :proteinuria should include :
- Measurement of- Measurement of serum creatinineserum creatinine
andand electrolyte panelelectrolyte panel
-- First morning urineFirst morning urine proteinprotein
:creatinine:creatinine
ratioratio
-- Serum albuminSerum albumin levellevel
-- ComplementComplement levels.levels. ""

I. Glomerular ProteinuriaI. Glomerular Proteinuria
"" Glomerular proteinuria canGlomerular proteinuria can rangerange fromfrom <1 g to<1 g to
>30 g/24 hr>30 g/24 hr.. ""
"" Glomerular proteinuria results fromGlomerular proteinuria results from alterations inalterations in
the permeabilitythe permeability of any of the layers of theof any of the layers of the
glomerular capillary wall to normally filteredglomerular capillary wall to normally filtered
proteins and occurs in a variety of renal diseases.proteins and occurs in a variety of renal diseases. ""
http://emedicine.medscape.com/article/984289-overvi

I. Glomerular Proteinuria (cont.)I. Glomerular Proteinuria (cont.)
"" Glomerular proteinuria should beGlomerular proteinuria should be suspectedsuspected
in any patient with:in any patient with:
- First morning- First morning urine protein : creatinineurine protein : creatinine
ratio >1.0ratio >1.0, or, or
- Proteinuria of any degree- Proteinuria of any degree, accompanied by:, accompanied by:
i.i. HypertensionHypertension
ii.ii. HematuriaHematuria
iii.iii. EdemaEdema oror
iv.iv. Renal dysfunctionRenal dysfunction ""

Disorders characterizedDisorders characterized primarily by proteinuriaprimarily by proteinuria
include:(include:(MAD MP2 SIFS))
IIdiopathic (minimal changediopathic (minimal change))
nephrotic syndromenephrotic syndrome
MMembranoembranoPProliferativeroliferative
glomerulonephritisglomerulonephritis
FFocalocal SSegmentalegmental
glomerulosclerosisglomerulosclerosis
AAmyloidosismyloidosis
MMesangialesangial PProliferativeroliferative
glomerulonephritisglomerulonephritis
DDiabetic nephropathyiabetic nephropathy
MMembranous nephropathyembranous nephropathy SSickle cell nephropathyickle cell nephropathy

Renal disorders thatRenal disorders that proteinuriaproteinuria can becan be a prominenta prominent
featurefeature includeinclude::
acute Postinfectious glomerulonephritis
Immunoglobulin A nephropathy
Lupus nephritis
Henoch-Schönlein purpura nephritis
Alport syndrome

DiagnosisDiagnosis
"" In asymptomatic patients with low-grade proteinuria
(protein: creatinine ratio 0.2-1.0) in whom all other
findings are normal, renal biopsy might not be
indicated because:
* Underlying process may be transient or
resolving or
*Specific pathologic features of a chronic
kidney disease might not yet be
apparent. Such patients should have
periodic re- evaluation (every 4-6 months
unless the patient is symptomatic) ""

DiagnosisDiagnosis ((Cont.)
"" Consisting of:Consisting of:
• Physical examinationPhysical examination andand bloodblood
pressurepressure determinationdetermination
• UrinalysisUrinalysis
• Measurement ofMeasurement of serum creatinineserum creatinine
• First morning voidedFirst morning voided urine protein :urine protein :
creatinine ratiocreatinine ratio.. ""

Indications for renal biopsyIndications for renal biopsy
"" Include:Include:
• Increasing proteinuriaIncreasing proteinuria
(protein : creatinine >1.0)(protein : creatinine >1.0)
and/orand/or
•TheThe development ofdevelopment of ::
i.i. HematuriaHematuria
ii.ii. HypertensionHypertension
iii.iii. Diminished renal functionDiminished renal function ""
1. http://www.hopkinschildrens.org/proteinuria.aspx
2. http://emedicine.medscape.com/article/984289-
overview#a30

ii. Tubular Proteinuria(cont.)ii. Tubular Proteinuria(cont.)
"" In the healthy stateIn the healthy state, large amounts of proteins of, large amounts of proteins of
lower molecular weight than albumin arelower molecular weight than albumin are filteredfiltered
by the glomerulusby the glomerulus andand reabsorbed in the proximalreabsorbed in the proximal
tubuletubule ""
"" A variety of renal disorders that primarilyA variety of renal disorders that primarily
involve the tubulointerstitial compartment of theinvolve the tubulointerstitial compartment of the
kidney can causekidney can cause low-grade fixed proteinurialow-grade fixed proteinuria
(protein : creatinine ratio(protein : creatinine ratio <1.0<1.0.. ""

"" Injury to the proximal tubulesInjury to the proximal tubules can result in:can result in:
• Diminished reabsorptive capacityDiminished reabsorptive capacity
• Loss of these low molecular weight proteinsLoss of these low molecular weight proteins
in the urinein the urine ""
"" Tubular proteinuria may be seen inTubular proteinuria may be seen in acquiredacquired
andand inherited disordersinherited disorders and may beand may be associated withassociated with
other defects of proximal tubular functionother defects of proximal tubular function, such as, such as
the Fanconi syndrome.the Fanconi syndrome.
(glycosuria, phosphaturia, bicarbonate(glycosuria, phosphaturia, bicarbonate
wasting, and aminoaciduria).wasting, and aminoaciduria). ""

"" AsymptomaticAsymptomatic patients having persistentpersistent
proteinuriaproteinuria generally have glomerular rather thanglomerular rather than
tubular proteinuriatubular proteinuria ""
"" Tubular proteinuria is a consistent finding among
patients with the X-linked tubular syndromeX-linked tubular syndrome, DentDent
diseasedisease, caused by mutations of the renal chloride
channel ""

ii. Tubularii. Tubular
Proteinuria(cont.)Proteinuria(cont.) Tubular diseasesTubular diseases
Cystinosis Heavy metal poisoning
Wilson disease Acute tubular necrosis
Lowe syndrome Renal dysplasia
Dent disease (X-linked
recessive nephrolithiasis)
Polycystic kidney disease
Galactosemia Reflux nephropathy
Tubulointerstitial nephritis

"" In occultIn occult cases , glomerular and tubularcases , glomerular and tubular
proteinuria can be distinguished byproteinuria can be distinguished by
electrophoresiselectrophoresis of the urine.of the urine. ""
"" InIn tubular proteinuriatubular proteinuria,, little or no albuminlittle or no albumin
is detected, whereas inis detected, whereas in glomerularglomerular
proteinuriaproteinuria thethe major protein is albuminmajor protein is albumin. ""

Asymptomatic proteinuria
Summary .1Summary .1
Hematuria or
other signs of
kidney disease
Nonrenal diseases Recheck
when resolves
Isolated proteinuria
Collected 12 –hr
Recumbent urine
>50mg/m2/12hr
Isolated intermittent
Proteinuria
or orthostatic proteinuria
Reassure
90%
No
No
Yes

Summary.2Summary.2
Hematuria or
other signs of
kidney disease
Nonrenal diseases
Collected 12 –hr
Recumbent urine
50-200mg/m2/12hr
Limited evaluation
BUN ,Creatinine
,S.electrolytes
Spot UPr: UCr ratio , S .Total
protein
C3 ,C4 ,ASOT, Lupus
serology (selected cases)
Renal imaging ,index of
tubular proteinuria
Follow
-up
5%
No
No
Normal

SummarySummary
Hematuria or
other signs of
kidney disease
Nonrenal diseases
Collected 12 –hr
Recumbent urine
<200mg/m2/12hr
50-200mg/m2/12hr
Limited evaluation
BUN ,Creatinine ,S.electrolytes
Spot UPr: UCr ratio , S .Total
protein
C3 ,C4 ,ASOT, Lupus serology
(selected cases)
Renal imaging ,index of tubular
proteinuria
•Evaluation
•Consider
referral
•S .Total
protein
•HIV status
•Fractionated
24-hr urine
collection
•S. Albumin
•S. Cholesterol
•ASOT
•C3,C4
•ANA ,
anti-DNA
•GFR
•Renal imaging
•Renal biopsy
Abnorm
al
Yes
5%
No
No

References
1. Mori Y, Hiraoka M, Suganuma N, Tsukahara H, Yoshida H, Mayumi M. Urinary creatinine
excretion and protein/creatinine ratios vary by body size and gender in children. Pediatr
Nephrol. May 2006;21(5):683-7.
2. American Academy of Pediatrics. Hagan JF, Shaw JS, Duncan PM, eds. Bright Futures:
Guidelines for Health Supervision of Infants, Children, and Adolescents. 3rd Ed. Elk
Grove, IL: American Academy of Pediatrics; 2008.
3. http://www.aafp.org/afp/2010/0915/p645.html
4. http://www.fpnotebook.com/Urology/Peds/PrtnrInChldrn.htm
5. http://www.hindawi.com/journals/ijped/2012/768142/
6. http://www.uptodate.com/contents/evaluation-of-proteinuria-in-children
7. http://www.hopkinschildrens.org/proteinuria.aspx
8. http://www.rightdiagnosis.com/symptoms/proteinuria_in_children/common.htm
9. http://emedicine.medscape.com/article/984289-overview#a30
10. http://brightfutures.aap.org/3rd_edition_guidelines_and_pocket_guide.html
11. http://www.annualreviews.org/doi/abs/10.1146/annurev.physiol.67.031103.154845?
journalCode=physiol

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