Proteinuria lecture

1. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 1
Proteinuria & Nephrotic Syndrome
ProfNagyAbdel-HadySayed-Ahmed
Plasma ProteinDeliveryto the Nephrons
• Proteinconc.inplasma = ~70 g/L
• Renal plasmaflow = 625 ml/min
• X 1440 (min/day) = ~900 L/day
• Proteindelivery/day = 63000 g/day
= 63 kg/day
Renal Handlingof Proteins
Despite the deliveryof manygramsof plasmaproteinstothe nephronseachday,proteinisnormally
presentinonlysmall quantitiesinthe urine –due to:
1. The glomerulusrestrictsthe filtrationof proteins
2. The tubulesreabsorbmostof the filteredproteins
GlomerularRestrictionof Proteinuia
Glomerularcapillariesare highlyefficientsievingfilter:
• Free water150-180 L/day + electrolytes&othersolutes(<10’000 Daltons) freelyfiltered
• Retainthe permeationof macromoleculesof the size orgreaterthanalbumin(cut-off 1.5nm)–
on the basisof size,charge,shape anddeformability
FiltrationBarrier
• Endothelial cellfenestra(1000A)

2. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 2
• -ve chargedBM: type IV collagennetworkfilledwithpolyanionicheparansulphate
proteoglycans
• -ve chargedepithelial cellswithfootprcesses(200-300A inbetween)coveredbyslit
diaphragmwithopenings4x14nm
• However,hemodynamicfactorsalsoplaya role inglomerularhandlingof macromolecules
Tubular Reabsorption
• 500-1000 mg of albuminisfilteredbythe glomerulieachday – yetonly20 mg/dayreachesthe
final urine,the balance beingabsorbedbythe proximal tubules
Many low-molecularweightproteinsandpeptidesare freelyfilteredbythe glomerulusandare
similarlyreabsorbed&degradedbythe renal tubules;e.g.lysozymes,ribonuclease,lightchains,b2
microglobulin,insulin,GH,& PTH
Barrier to AlbuminFiltration
• Albuminisa relativelysmall molecules:MW 69000 Daltons,Radius5.5 nm.Moleculesof such
size maybe filterable
• However,asall the layersof the filtrationmembrane are –velychargedandthe albuminisan
anionicmoleculeitisvirtuallyexcludedfrom the Gfiltrate byelectronegative repellentforces
Normal Urinary ProteinExcretion
• Normally,urinaryproteinexcretionis<150 mg/dayin adults& <140 mg/m2
/dayinchildren
• It isusuallynotdetectedbyordinarymethods
• It iscomposedof :
– Mucoproteins(Tamm-Horsfall glycoprotein):70 mg
– Bloodgrouprelatedsubstances:35 mg
– Albumin: 16 mg
– Immunoglobulin:6mg

3. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 3
– Mucopolysaccharides:16 mg
– Otherptnse.g.hormones& enzymes:v.small amounts
49%
24%
11%
4% 11%
1%
Tamm-Horsfall Bl Gp related subst
Albumin Igs
Mucopolysaccharides Others
Composition of Normal Urinary Proteins
<150mg/day
Proteinuria
(Pathological Proteinuria)
• Proteinuriaisanabnormallyhighamountof proteininurine:>150 mg/day
• Grades:
– Microalbuminuria:30-300 mg/day(albumin) =(20-200 ug/min)
– Mildproteinuria:<1000 mg/day
– Moderate proteinuria:1000-2000 mg/day
– Heavyproteinuria:>2000 mg/day
– Nephroticrange proteinuria:>3500 mg/day

4. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 4
The KidneyDisease OutcomesQualityInitiative(K/DOQI) of the National KidneyFoundation(NKF)
Feb 2002 Am J Kidney Dis. 2002;39:1-246
Mechanismof Proteinuria
• Alteredglomerularpermeability:increased filtrationof normal plasmaproteinsespalbumin –
glomerularproteinuria
• Failure of the tubulestoreabsorbthe small amountof the normallyfilteredproteins –tubular
proteinuria
• G. filtrationof abnormal LMW ptnsin amountsthat exceedstubularreabsorptive capacity –
overflowproteinuria
• Increasedsecretionof uroepithelial mucoptns.andsecretoryIgA inresponse toirritation –
secretotyproteinuria
Proteinuriavs. Albuminuria
• Proteinuriaisthe excretionof differentsubtypesof proteinsincludingalbumininurine –most
testsdetectproteinuriaratherthatalbuminuria
• Albuminuriareferstothe amountof albuminexcretedinurine.Itconstitutesthe major
fractionof proteinuriainglomerulardisease,hypertensive anddiabeticproteinuriabutnotin

5. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 5
mildtomoderate proteinuriaof tubulardisease oroverflow proteinuria –Itneedsspecific
(?expensive)reagentse.g.RIA
Pathogenesis of Proteinuria
1- GlomerularProteinuria
• Mechanism:
– Hemodynamic:increase PGC,increase GFR
– Increase G. permeability:
• Basementmembrane injury
• Endothelial orepithelial cell injury
• Loss of electrostaticcharge barrier
In Minimal Change Disease albuminuriaisdue toimpaired charge selectivity,whileinotherGNsthe
defectisinthe size selective seiving
• The proteininurine islarge macromolecularproteins,mainly albuminanditcan be mildto
heavy
2- Tubular Proteinuria
• Impairedtubularreabsorptionof filteredproteins
• Proteins:LMW proteins,lysozymes,b2-microglobulin,Tamm-Horsfallprotein,aswell as
albumin
• Almostalwaysmild:usually<1g/day;rarelyexceeds2g/day
3- OverflowProteinuria
• Pts have norenal disease butoverproductionof small proteins
• Lightor heavychainsof Igsin monoclonal gammopathiese.g.MM“Bence Jonesproteinuria”
• Lysozymesinmyelomonocyticleukemia
• Myoglobininrhabdomyolysis

6. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 6
• Hemoglobinfollowinghemolysis
• Amylase inpancreatitis
4- Secretory Proteinuria
• IncreaseduroepithelialmucoproteinsandsecretoryIgA
• It needsspecificandsensitive technique fordetection
• However,ita component(togetherwiththe tubularproteinuria) of the mildproteinuriathat
occurs inacute or chronictubulointerstitial diseases
Bence JonesProteinuria
• Bence Jonesprotein isthe lightchainfractionof immunoglobulin
• It appearsinabnormal amountsinurine incases of multiple myeloma
• It clotsat temperature 45-55°C, above andbelow thatrange itdissolvesinurine.
• shouldbe confirmedbyimmunoelectro-phoresis
The causes of Bence Jone'sproteinuriainclude
– multiple myeloma,
– amyloidosis,
– adultFanconi syndrome,
– benignmonoclonal
gammopathy
– hyperparathyroidism.
Measurementof Proteinuria
Qualitative techniquesPrecipitationtechniques:
• Precipitationtechniques:
– Heating,or addingglacial aceticacid,conc.nitricacid, trichloroaceticacidor
sulfosalicylicacid(SSA,the mostpopular)
– SSA:3% SSA + equal amountof urine;turbiditymaybe gradedby comparingto(urine
+ water):trace=20mg/dl,4+=1g/dl –or measuredbyturbidometry

7. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 7
– It detectsbothalbumin,globulinandBJproteins
– +ve precipitationwithnegative dipstickinglobulinuriaorBJ proteinuria
• Dipstick:tetrabromophenolphthaleinpHindicator+pH buffor –proteinsinduce acolorchange
– Sensitivetoalbuminmore thanotherproteins
• conc. 10-15 mg/dl may produce trace color,andabove 30 mg/dl gives
+ve results
– It islesssensitivetoglobulinandmucoproteinsandfailstodetectBence Jones
proteinuria
– May be usedsemiquantitative:
• Trace: <30, 1+:>30, 2+: >100, 3+: >500 mg/dl
• False +ve:highSG, alkaline urine,UTI,antiseptics
• Othermethods:
– Kjeldahl measurementof precipitatednitrogen:the reference andresearchmethod
(10-20 mg/dl)
– Biuretmethod:copperreagent –measure peptide bonds(50mg/dl)
– Dye-bindingmethodse.g.Coomassie brilliantblue (50-100mg/dl)
Quantitative techniques:
– Total 24-hoururinaryprotein
– Overnighturinaryprotein
– Urinary protein/creatinine (UPr/Cr) ratio(mg/mgorg/g)
– Urinary albumin/creatinineratioismore accurate,especiallyinlow-rangeproteinuria
(<500 mg/d) but more expensive andlesspractical
Urinary Protein/Creatinine & Albumin/Creatinine Ratios
• mg/mgor g/g (sometimesmg/gormg/mole)
• Anyrandom urine sample butpreferablythe 1st
or 2nd
morningsample
• Normal U Pr/Cr rationis <0.2

8. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 8
• Normal U Alb/Crrationis <0.05
Severity
Urinary Pro/Creat
Or Alb/Creat Ratio (g/g)
Normal proteinuria<0.2 or <0.03
Mild proteinuria<1.0
Moderate proteinuria1.0 – 2.0
Severe proteinuria2.0 – 3.5
Nephrotic range proteinuria>3.5
False Positive / False Negative Proteinuria
• False +ve:whenurine isalkaline andveryconcentrated; orif the stick testisleftinurine for
longtime
• False –ve:whenproteinexcretionismainlyBenceJonesproteinuriaorwhenurine isvery
diluted
Cause of Proteinuriaas Relatedto Quantity
CauseDaily protein excretion
Mild glomerulopathies
Tubular proteinuria
Overflow proteinuria
0.15 to 2.0 g
Usually glomerular2.0 to 4.0 g
Always glomerular>4.0 g

9. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 9
SelectivityofProteinuria
• An attempttoassessglomerularsize orcharge discrimination
• e.g.compare the clearance of large molec.IgG withthat of small ones(albuminortransferrin):
CIgG/Ctransferrin
• Ratio>0.2 = non-selective,<0.1= selective
• Distinguishminimalchange NSfromotherformsof glomerulardisease
• Little use of such testsismade today
Significance ofProteinuria
Proteinuria
Disease-
RelatedIsolated
Hematuria, urinary sediment, hypertension,
↓ GFR, DM, collagen vascular diseases or
other conditions
Proteinuria
PersistentTransient
intermittent
2-6 months retesting
Proteinuria
SevereMild
<1-1.5 g/day >2.5-3 g/day
Proteinuria
Disease-
RelatedIsolated
PersistentTransient
SevereMild

10. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 10
Proteinuria
Clinical Classification
• Isolatedproteinuria:
– Benignisolatedproteinuria
• Functional proteinuria
• Idiopathictransient
proteinuria
• Intermittent
proteinuria
• Orthostatic(postural)
proteinuria
– Persistent(serious) isolatedproteinuria
• Proteinuriaassociatedwithrenal orsystemicdisease
Functional Proteinuria
• Proteinuriainassociationwithhighfever,strenuousexercise,exposure tocold,emotional
stress,congestive heartfailure,andotheracute medical diseases
• Proteinuriadisappearsassoonasthe precipitating factorshasresolved
• It isglomerularintype due tochangesin renal hemodynamics
• No progressive renaldisease
Orthostatic (Postural) Proteinuria
• Proteinuriapresentinthe uprightpositiononlythatdisappearswithrecumbentposition
• Mostlybelow2g/day– occasionallyheavier
• 90% of youngmenwithisolatedproteinuria
• Entirelybenign,transientin80%
PersistentIsolatedProteinuria
• Isolatedproteinuriapersistentinall samplestestedinbothrecumbentanduprightstates

11. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 11
• 5-10% of isolatedproteinuriainhealthymen
• Almostalwaysasignof structure renal disease withsome riskof progression –although
prognosisisnotbad inall cases
• A wide varietyof renal lesions;e.g.GN
Disease-RelatedProteinuria
Renal or Systemic
• Non-nephrotic–range proteinuria(<3.5 g/24 hours);
– Mildglomerulardisease
– Tubulointerstitial disease
– Acute tubularnecrosis
– Hypertension
– Collagenvasculardiseases
– Multiple myeloma
– Bacterial endocarditis
• Nephrotic-rangeproteinuria(>3.5 g/24 hours):
– Primaryglomerulopathies
• Minimal change
disease
• Membranous
glomerulonephritis
• Focal-segmental
glomerulonephritis
• ImmunoglobulinA
nephropathy
• Membranoproliferativ
e glomerulonephritis
– Secondaryglomerulopathies
• Acute poststreptococcal
glomerulonephritis
• Collagenvasculardiseases,
HUS, TTP
• Metabolicdiseases:DM,
Amyloidosis, etc.
• Malignancy-associated
• Drugs (gold,nonsteroidal
anti-inflammatorydrugs,
heroin,penicillamine)

12. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 12
• Infections(human
immunodeficiencyvirus;
hepatitisA,B,C)
• Obesity
• Reflux nephropathy
Tubulointerstitial Diseases Causingproteinuria
Hereditary
• Cystinosis
• Galactosemia
• Lowe Syndrome
• MedullaryCysticKidney
• Proximal RTA
• WilsonDisease
Non-Hereditary
• Acute TubularNecrosis*
• analgesicabuse
• antibiotics
• cysticdiseases
• heavymetal poisoning
• homograftrejection
• hypokalemia
• interstitialnephritis
• penicillamine
• reflux
Symptoms & Signs of Proteinuria
• Usuallydetectedinitiallyonroutine urinalysisasanunexpectedfinding
• Patientsmaybe completelyasymptomatic
• Or may have manysymptomsaccordingto the magnitude of the proteinuriaand/orthe level
of renal function
• Foamyor frothyurine
• Varyinggradesof edema

13. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 13
• Nephroticsyndrome:proteinuria>3.5grams/dayclassicallypresentswithedema,
hypoalbuminemia,andhypercholesterolemia
• Patientswithglomerulonephritismaybe asymptomaticorhave hematuria,edemaof new
onset,pulmonarysymptoms,hypertensionand/orazotemia
Complicationsof Proteinuria
• Hypoalbuminemia
• Edema
• Increasedhepaticlipoproteinsynthesis
• Increasedplateletaggregability
• Increasedtubularproteinreabsorption
• Possible tubulardysfunction
• Tubulardamage
• Loss of proteinscarryingvitamins,
hormonesandminerals
• Trace mineral deficiencies
• VitaminDdeficiency
• Loss of immunoglobulins
• Reducedcellularimmunity
• Increasedsusceptibilitytoinfection
• Athersclerosis,CAD,&CVD
• Alterationsincoagulationfactors
• Spontaneousthromboembolism
• Renal veinthrombosis
• Negative nitrogenbalance
• Malnutrition
• Alterationindrugmetabolism
• Hypocalcemia
Proteinuriaand Progressionof CKD
• Persistentlyincreasedproteinexcretionisusuallyamarkerof kidneydamage
• Proteinuriaisagoodpredictorof progressive CRF (Williamsetal.QJM 1988,67:343-54)
• the rate of decline of renal functionwasproportionaltothe severityof proteinuria (Locatelli
et al.Nephrol Dial Transpl 1996.11:461-7)
• transudationof proteinandproteinaceousmaterial →glomerularcellsproliferationand
increase synthesisof extracellularmatrix (ECM) components

14. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 14
SelectedInvestigationstoBe ConsideredinProteinuria
Interpretation of findingTest
Elevated in systemic lupus erythematosusANA
Elevated after streptococcal glomerulonephritisASO titer
Levels are low in glomerulonephritidesC3 and C4
If normal, helps to rule out inflammatory and infectious causesESR
Elevated in DMFBG
Low in CRFHb, Hct,
Albumin decreased and cholesterol increased NSS. albumin and lipid
a screening for any abnormalities following renal diseaseSerum electrolytes
elevated urate can cause TIN or stoneSerum urate
HIV, hepatitis B and C, and syphilis have been associated with
glomerular proteinuria
HIV, VDRL, and
hepatitis serologic
Results are abnormal in multiple myeloma
S. and U protein
electrophoresis
structural renal diseaseRenal US
evidence of systemic diseaseChest X ray
Pathological evidence of diseaseRenal Biopsy
Approach to Proteinuria

15. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 15
Proteinuria found on testing–1
•Repeat test x 2-3
•Early morning urine
•Physical examination & BP
•Fever or
exercise
•Test now
negative
Reassure &
Discharge
•No ptnuria in morning
sample
•Present during day
•Assess BP,
PCr, Renal US
•Persistent isolated
proteinuria
•Persistent
proteinuria +
Hematuria
Proteinuria found on testing–2
Reassure &
Discharge
•Persistent isolated
proteinuria
•Assess BP, PCr,
•Quantitate Ptnuria, GFR, Autoimmune
• Renal US
•Reassure
watch, Rechck
6-monthly
If all normal
•Pturia
disappear or
intermittent
•Persistent proteinuria +
Hematuria or syst. Dis.
If abnormal
Kidney
Biopsy
Nephrotic Syndrome
Definition
• Massive lossof urinaryprotein(primarilyalbuminuria) leadingtohypoproteinemia
(hypoalbuminemia) anditsresult,edema.
• Hyperlipidemia,hypercholesterolemia,andincreasedlipiduriaare usuallyassociated.
• Althoughnotcommonlythoughtof aspart of the syndrome,hypertension,hematuria,and
azotemiamayoccur
Glomerular Damage
Proteinuria
Hypoalbuminemia
Decreased plasma oncotic pressure
Starling Forces
EDEMA
Decreased effective
circulatory volume ↑ADH↑RAS, ↓ANP

16. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 16
Pathology
• Most commonpathologiesof NS
– Minimal change NS(MCNS)
– Focal segmental glomerulosclerosis(FSGS)
– Membranoursglomerulonephritis(MGN)
– Membranoproliferative GN (MPGN)
• Morbidityissubstantial andprogressiontoESRDdependsonthe degree of proteinuriaaswell
as the type of disease
Causes
• 1ry glomerulardisease (noidentifiable cause)
• 2ry NSdue to any of the following:
– Infectionorposinfection(Schistosoma,Malaria,HCV,HBV,…etc.)
– Drugs: gold,penicillamin,NSAIDs,…etc.

17. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 17
– Metabolic:diabetesmellitus,amyloidosis,…etc.
– Collagen&Autoimmune disease:SLE,Vasculitis,…etc.
– Malignancy:Lymphoma,Multiple Myeloma,…etc.
– Renal veinthrombosis
– Congenital andfamilial conditions
– 2ry toother conditions(e.g.PET)
NephroticSyndrome and Pregnancy
• The most commoncause in late preg.is Pre-EclampticToxaemia
• Othercauses:1ry & other2ry glomerulopathies
– MembranousN,Prolif GN,MPGN, MCD, LupusNephritis,HereditaryN,DiabeticN,
Renal VeinThrombosis,Amyloidosis,….etc.,
Managementof Proteinuria& NephroticSyndrome
 TTT of the underlyingdisease isthe 1rygoal of therapy
 Some formsof glomerulardisease mayhave nospecifictreatment!
 Severe proteinuriamaynecessitatestherapytoreduce the proteinexcretionspecifically
 Dietaryproteinrestriction:the lowestallowableproteinrestrictionis0.6g/kg/dayplusprotein
addedto match urinarylosses
 ↓ BP:dietarysaltrestriction,diuretics&otheranti-Htn
 ACE inhibitorsorARBs:reduce proteinbyloweringefferentarteriolarresistance;alsoadirect
effectonglomerularpermselectivity
 However,ACEinhibitorscould cause ↑ inthe patient'sserumcreatinine,↑ inS.K+
,and acute
renal failure
 NSAIDsinhighdoses:↓ GFR & proteinuria –side effects:renal failure,GITbleeding&↑ S.K+
;
not frequentlyused

18. Proteinuria & Nephrotic Syndrome Lecture by ProfNagyAbdel-Hady
Sayed-Ahmed
Page | 18
 Aggressive tttto↓ massive edemaandanasarca,prevention of thromboembolism, ↓
hyperlipidemia
 Cautioususe of diuretics(↓ volume andthromboembolism)
 TTT of complications:Antibioticsforinfections,anticoagulationforthrombosis,proper
nutrition
 Salt pooralbumin isexpensive andislostquicklyinurine. Sogivenonlyinsevereresistant
oedema
 Corticosteroidsandimmunosuppressivesare givenonlyinsusciptilble 1ryor2ry GN after
kidneybiopsyinadultsorempricallyinchildren
Good Luck
ProfNagyAbdel-HadySayed-Ahmed