Page 1Introduction to theIntroduction to theChild with ProteinuriaChild with ProteinuriaProf. Dr.Prof. Dr.Saad S Al AniSaad S Al AniSenior PediatricSenior PediatricconsultantconsultantHead of PediatricHead of PediatricDepartmentDepartmentKhorfakkanKhorfakkanhospitalhospitalSharjah ,UAESharjah ,UAEsaadsalani@yahoo.com
Page 3IntroductionIntroduction""The demonstration of proteinuria on a routineThe demonstration of proteinuria on a routinescreening urinalysis isscreening urinalysis is commoncommon """" Protein can be found in the urine of healthyProtein can be found in the urine of healthychildren , with a reasonablechildren , with a reasonable upper limitupper limit beingbeing150mg/24hr150mg/24hr ((4 mg/m2/hr4 mg/m2/hr)) ""1. http://www.aafp.org/afp/2010/0915/p645.html2. http://emedicine.medscape.com/article/984289-overview
Page 4Cont.Cont.""10%10% of children aged 8-15 yr testof children aged 8-15 yr test positivepositive forforproteinuria 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/hrSignificantSignificant values :values : 4–40 mg/m2/hr4–40 mg/m2/hrNephroticNephrotic range:range: >40 mg/m2/hr>40 mg/m2/hr ""http://brightfutures.aap.org/3rd_edition_guidelines_and_pocket_
Page 5Cont.Cont."" Assess completeness of 24-hour collectionAssess completeness of 24-hour collectionby simultaneously measuringby simultaneously measuring urineurinecreatininecreatinine :: ≥15 mg/kg body weight≥15 mg/kg body weight ininaa 24-hour collection24-hour collection"""" The challenge is to differentiate the childThe challenge is to differentiate the childwithwith proteinuria related to renal diseaseproteinuria related to renal disease fromfromthe otherwisethe otherwise healthy child with transienthealthy child with transient ororotherother benign forms of proteinuriabenign forms of proteinuria""
Page 6Urinary dipstick testUrinary dipstick test"" DipsticksDipsticks primarily detectprimarily detect albuminuriaalbuminuriaand areand are less sensitive for otherless sensitive for other forms offorms ofproteinuria: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 qualitativeassessment of urinary protein excretionassessment of urinary protein excretion""http://www.fpnotebook.com/Urology/Peds/PrtnrInChldrn.htm
Page 8Cont.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 predominanturinary protein is not albuminurinary protein is not albumin""http://www.hopkinschildrens.org/proteinuria.aspx
Page 9Cont.Cont."" False-positive testFalse-positive test results may be seen withresults may be seen with11.Gross hematuria.Gross hematuria2. Contamination with2. Contamination with antiseptic agentsantiseptic agentsi. Chlorhexidinei. Chlorhexidineii. Benzalkonium chlorideii. Benzalkonium chlorideiii. Hydrogen peroxideiii. Hydrogen peroxide33.Urinary pH >7.0.Urinary pH >7.044.Phenazopyridine therapy.Phenazopyridine therapy""http://www.hopkinschildrens.org/proteinuria.aspx
Page 10"" Because the dipstick reactionBecause the dipstick reaction offers onlyoffers onlya qualitative measurementa qualitative measurement of urinaryof urinaryprotein excretion, children withprotein excretion, children withpersistent proteinuriapersistent proteinuria should haveshould haveproteinuria quantitatedproteinuria quantitated with the morewith the morepreciseprecise spot urine protein: creatininespot urine protein: creatinineratio (UPr : UCr)ratio (UPr : UCr) ""Cont.Cont.
Page 11"" ThisThis ratioratio isis calculated by dividingcalculated by dividing thetheUPr (mg/dL) concentration by the UCrUPr (mg/dL) concentration by the UCr(mg/dL) concentration(mg/dL) concentration and is bestand is bestperformed on aperformed on a first morning voided urinefirst morning voided urinespecimenspecimen to eliminate the possibility ofto eliminate the possibility oforthostatic (postural) proteinuriaorthostatic (postural) proteinuria ""Cont.Cont.
Page 12"" 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 agesuggestsuggest 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 shownto have ato have a high correlation withhigh correlation withprotein excretion determinationsprotein excretion determinations inintimed urine collectiontimed urine collection ""
Page 13"" DefinedDefined as the presence of albumin in theas the presence of albumin in theurine above the normal level but belowurine above the normal level but belowthe detectable range of conventional urinethe detectable range of conventional urinedipstick methodsdipstick methods ""MicroalbuminuriaMicroalbuminuria"" TheThe mean level of albumin excretionmean level of albumin excretion hashasbeen shown fall betweenbeen shown fall between 8 and 10 mg/g8 and 10 mg/gcreatininecreatinine in childrenin children >6 yr old>6 yr old ""http://www.hopkinschildrens.org/proteinuria.aspx
Page 14Cont.Cont."" Microalbuminuria in children has beenMicroalbuminuria in children has beenfound to befound to be associated with obesityassociated with obesity andandtoto predictpredict, with reasonable specificity,, with reasonable specificity,thethe development of diabetic nephropathydevelopment of diabetic nephropathyinin type 1 diabetes mellitustype 1 diabetes mellitus ""
Page 15Causes of proteinuriaCauses of proteinuria
Page 16"" The majority of children found to haveThe majority of children found to havepositive urinary dipstick values for proteinpositive urinary dipstick values for proteinhavehave normal dipstick values on repeatednormal dipstick values on repeatedmeasurementsmeasurements ""1.Transient Proteinuria1.Transient Proteinuria"" ApproximatelyApproximately 10%10% of children whoof children whoundergoundergo random urinalysisrandom urinalysis havehave proteinuriaproteinuriaby a single dipstick measurementby a single dipstick measurement.. ""
Page 171.Transient Proteinuria(cont.)1.Transient Proteinuria(cont.)"" Across the school-age spectrum thisAcross the school-age spectrum thisfinding occurs morefinding occurs more commonly incommonly inadolescentsadolescents than in younger childrenthan in younger children """" In mostIn most cases, serial testing of thecases, serial testing of thepatient’s urine demonstratespatient’s urine demonstrates resolutionresolutionof the abnormality.of the abnormality. ""http://emedicine.medscape.com/article/984289-overv
Page 181.Transient Proteinuria(cont.)1.Transient Proteinuria(cont.)"" The proteinuria usuallyThe proteinuria usually doesdoesnot 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 failureDehydration SeizuresCold exposure Stress"" No evaluation or therapyNo evaluation or therapy is neededis needed ""
Page 19"" Orthostatic proteinuria is theOrthostatic proteinuria is the mostmostcommon cause of persistent proteinuriacommon cause of persistent proteinuria ininschool-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 withpersistent proteinuriapersistent proteinuria ""http://emedicine.medscape.com/article/984289-overview#
Page 202.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)"" Patients with orthostatic proteinuriaPatients with orthostatic proteinuriaexcrete normal or minimally increasedexcrete normal or minimally increasedamountsamounts of protein in theof protein in the supine positionsupine position.. """" Children with this condition areChildren with this condition are usuallyusuallyasymptomaticasymptomatic, and the condition is, and the condition is discovereddiscoveredon routine urinalysison routine urinalysis.. ""
Page 21"" In theIn the upright positionupright position, urinary protein, urinary proteinexcretion may beexcretion may be increased 10-foldincreased 10-fold, up, upto 1,000 mg/24 hr (1 g/24 hr).to 1,000 mg/24 hr (1 g/24 hr). ""2.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)""Hematuria, hypertension, hypoalbuminemia,Hematuria, hypertension, hypoalbuminemia,edema, and renal dysfunctionedema, and renal dysfunction are absentare absent.. ""
Page 222.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)"" The initial evaluation should include anThe initial evaluation should include anassessment for orthostatic proteinuriaassessment for orthostatic proteinuria, a, acondition in which thecondition in which the 24-hr urinary protein24-hr urinary proteinexcretion rarely exceeds 1 gexcretion rarely exceeds 1 g ""
Page 232.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)"" It begins with the collection of aIt begins with the collection of a firstfirstmorning urine samplemorning urine sample, with subsequent, with subsequenttesting of any urinary abnormalities by atesting of any urinary abnormalities by acomplete urinalysiscomplete urinalysis andand determination of adetermination of aspot protein : creatinine (Pr : Cr) ratiospot protein : creatinine (Pr : Cr) ratio. ""
Page 242.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)"" TheThe absence of proteinuriaabsence of proteinuria (dipstick(dipsticknegative 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 urinesample forsample for 3 consecutive days confirms3 consecutive days confirms thethediagnosis of orthostatic proteinuriadiagnosis of orthostatic proteinuria """" TheThe correct collectioncorrect collection of theof the first morningfirst morningurineurine sample issample is criticalcritical.. ""
Page 252.Orthostatic (Postural) Proteinuria (cont.)2.Orthostatic (Postural) Proteinuria (cont.)"" TheThe causecause of orthostatic proteinuria isof orthostatic proteinuria isunknownunknown, although, althoughi. Altered renal hemodynamicsi. Altered renal hemodynamicsii. Partial renal vein obstruction inii. Partial renal vein obstruction inthe upright position arethe upright position are possiblepossiblecausescauses.. """" NoNo further evaluation is necessary, and thefurther evaluation is necessary, and thepatient and family should bepatient and family should be reassuredreassured ofofthethe benign naturebenign nature of this condition.of this condition. ""
Page 263.Fixed Proteinuria3.Fixed Proteinuria"" Fixed proteinuriaFixed proteinuria indicates renal diseaseindicates renal diseaseand 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 morningurine sampleurine sample onon 3 consecutive days3 consecutive days (>1+(>1+on dipstick ,urine specific gravity >1.015on dipstick ,urine specific gravity >1.015or protein : creatinine ratio >0.2)or protein : creatinine ratio >0.2) ""
Page 27Initial evaluationInitial evaluation"" Initial evaluation of a child with fixedInitial evaluation of a child with fixedproteinuria should include :proteinuria should include :- Measurement of- Measurement of serum creatinineserum creatinineandand electrolyte panelelectrolyte panel-- First morning urineFirst morning urine proteinprotein:creatinine:creatinineratioratio-- Serum albuminSerum albumin levellevel-- ComplementComplement levels.levels. ""
Page 28I. 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 inthe permeabilitythe permeability of any of the layers of theof any of the layers of theglomerular capillary wall to normally filteredglomerular capillary wall to normally filteredproteins and occurs in a variety of renal diseases.proteins and occurs in a variety of renal diseases. ""http://emedicine.medscape.com/article/984289-overvi
Page 29I. Glomerular Proteinuria (cont.)I. Glomerular Proteinuria (cont.)"" Glomerular proteinuria should beGlomerular proteinuria should be suspectedsuspectedin any patient with:in any patient with:- First morning- First morning urine protein : creatinineurine protein : creatinineratio >1.0ratio >1.0, or, or- Proteinuria of any degree- Proteinuria of any degree, accompanied by:, accompanied by:i.i. HypertensionHypertensionii.ii. HematuriaHematuriaiii.iii. EdemaEdema ororiv.iv. Renal dysfunctionRenal dysfunction ""
Page 31I. Glomerular Proteinuria (cont.)I. Glomerular Proteinuria (cont.)Renal disorders thatRenal disorders that proteinuriaproteinuria can becan be a prominenta prominentfeaturefeature includeinclude::acute Postinfectious glomerulonephritisImmunoglobulin A nephropathyLupus nephritisHenoch-Schönlein purpura nephritisAlport syndrome
Page 32DiagnosisDiagnosis"" In asymptomatic patients with low-grade proteinuria(protein: creatinine ratio 0.2-1.0) in whom all otherfindings are normal, renal biopsy might not beindicated because:* Underlying process may be transient orresolving or*Specific pathologic features of a chronickidney disease might not yet beapparent. Such patients should haveperiodic re- evaluation (every 4-6 monthsunless the patient is symptomatic) ""
Page 33DiagnosisDiagnosis ((Cont.)"" Consisting of:Consisting of:• Physical examinationPhysical examination andand bloodbloodpressurepressure determinationdetermination• UrinalysisUrinalysis• Measurement ofMeasurement of serum creatinineserum creatinine• First morning voidedFirst morning voided urine protein :urine protein :creatinine ratiocreatinine ratio.. ""
Page 34Indications 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. HematuriaHematuriaii.ii. HypertensionHypertensioniii.iii. Diminished renal functionDiminished renal function ""1. http://www.hopkinschildrens.org/proteinuria.aspx2. http://emedicine.medscape.com/article/984289-overview#a30
Page 35ii. Tubular Proteinuria(cont.)ii. Tubular Proteinuria(cont.)"" In the healthy stateIn the healthy state, large amounts of proteins of, large amounts of proteins oflower molecular weight than albumin arelower molecular weight than albumin are filteredfilteredby the glomerulusby the glomerulus andand reabsorbed in the proximalreabsorbed in the proximaltubuletubule """" A variety of renal disorders that primarilyA variety of renal disorders that primarilyinvolve the tubulointerstitial compartment of theinvolve the tubulointerstitial compartment of thekidney can causekidney can cause low-grade fixed proteinurialow-grade fixed proteinuria(protein : creatinine ratio(protein : creatinine ratio <1.0<1.0.. ""
Page 36ii. Tubular Proteinuria(cont.)ii. Tubular Proteinuria(cont.)"" 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 proteinsin the urinein the urine """" Tubular proteinuria may be seen inTubular proteinuria may be seen in acquiredacquiredandand inherited disordersinherited disorders and may beand may be associated withassociated withother defects of proximal tubular functionother defects of proximal tubular function, such as, such asthe Fanconi syndrome.the Fanconi syndrome.(glycosuria, phosphaturia, bicarbonate(glycosuria, phosphaturia, bicarbonatewasting, and aminoaciduria).wasting, and aminoaciduria). ""
Page 37ii. Tubular Proteinuria(cont.)ii. Tubular Proteinuria(cont.)"" AsymptomaticAsymptomatic patients having persistentpersistentproteinuriaproteinuria generally have glomerular rather thanglomerular rather thantubular proteinuriatubular proteinuria """" Tubular proteinuria is a consistent finding amongpatients with the X-linked tubular syndromeX-linked tubular syndrome, DentDentdiseasedisease, caused by mutations of the renal chloridechannel ""
Page 39ii. Tubular Proteinuria(cont.)ii. Tubular Proteinuria(cont.)"" In occultIn occult cases , glomerular and tubularcases , glomerular and tubularproteinuria can be distinguished byproteinuria can be distinguished byelectrophoresiselectrophoresis of the urine.of the urine. """" InIn tubular proteinuriatubular proteinuria,, little or no albuminlittle or no albuminis detected, whereas inis detected, whereas in glomerularglomerularproteinuriaproteinuria thethe major protein is albuminmajor protein is albumin. ""
Page 43References1. Mori Y, Hiraoka M, Suganuma N, Tsukahara H, Yoshida H, Mayumi M. Urinary creatinineexcretion and protein/creatinine ratios vary by body size and gender in children. PediatrNephrol. 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. ElkGrove, IL: American Academy of Pediatrics; 2008.3. http://www.aafp.org/afp/2010/0915/p645.html4. http://www.fpnotebook.com/Urology/Peds/PrtnrInChldrn.htm5. http://www.hindawi.com/journals/ijped/2012/768142/6. http://www.uptodate.com/contents/evaluation-of-proteinuria-in-children7. http://www.hopkinschildrens.org/proteinuria.aspx8. http://www.rightdiagnosis.com/symptoms/proteinuria_in_children/common.htm9. http://emedicine.medscape.com/article/984289-overview#a3010. http://brightfutures.aap.org/3rd_edition_guidelines_and_pocket_guide.html11. http://www.annualreviews.org/doi/abs/10.1146/annurev.physiol.67.031103.154845?journalCode=physiol