A classroom presentation on proteinuria

1. Proteinuria-Proteinuria-
How To Approach?How To Approach?
Presented by-Presented by-
Dr Jheelam BiswasDr Jheelam Biswas
RMO, Nephrology unit 1RMO, Nephrology unit 1

2. DefinitionDefinition
 Normal rate of albumin excretion is < 20Normal rate of albumin excretion is < 20
mg/day (15 mcg/min), increases with agemg/day (15 mcg/min), increases with age
and higher body weightand higher body weight
 However, early renal disease is reflected byHowever, early renal disease is reflected by
lesser degrees of proteinurialesser degrees of proteinuria
 Proteinuria is defined as protein excretionProteinuria is defined as protein excretion
>150mg/day.>150mg/day.

3. 70 mg/d
5
mg/d
10 mg/d 15 mg/d
15 mg/d
35 mg/d
Tamm Horsfall Protein Blood Group Related Antigens
Albumin Mucopolysaccarides
Hormones and Enzymes Immunoglobulins
Composition Of Urinary ProteinComposition Of Urinary Protein

4. 70 mg/d
5
mg/d
10 mg/d 15 mg/d
15 mg/d
35 mg/d
Tamm Horsfall Protein Blood Group Related Antigens
Albumin Mucopolysaccarides
Hormones and Enzymes Immunoglobulins
Mechanism of ProteinuriaMechanism of Proteinuria

5. Mechanism of ProteinuriaMechanism of Proteinuria
CausesCauses PATHOPHYSIOLOGIC FEATURESPATHOPHYSIOLOGIC FEATURES
Glomerular
defect causing albuminuria
(>70%) and HMW proteinuria.
Tubular
deficiency reabsorption of
proteins in proximal tubule
causing mostly LMW proteinuria
Overflow
excess serum concentrations of
protein overwhelm nephron’s
ability to reabsorb.

6. Classification Of ProteinuriaClassification Of Proteinuria
01.ACCORDING TO QUANTITY:01.ACCORDING TO QUANTITY:

7. Classification Of ProteinuriaClassification Of Proteinuria
• According to nature-According to nature-
• Functional-Functional- Proteinuria up to 500 mg/24 hProteinuria up to 500 mg/24 h
without the presence of awithout the presence of a kidney diseasekidney disease isis
called functional proteinuria. Eg-called functional proteinuria. Eg-
 Fever,Fever,
 Physical activity,Physical activity,
 Heat or cold,Heat or cold,
 Heart failure,Heart failure,
 orthostatic proteinuriaorthostatic proteinuria

8. Classification Of ProteinuriaClassification Of Proteinuria
 MicroalbuminuriaMicroalbuminuria-- is the presence ofis the presence of
more than 30 mg and up 300 mg albuminmore than 30 mg and up 300 mg albumin
in a 24-h urine collection. Eg.in a 24-h urine collection. Eg.
 Diabetic nephropathy,Diabetic nephropathy,
 Hypertensive NephropathyHypertensive Nephropathy

9. Classification Of ProteinuriaClassification Of Proteinuria
 Glomerular proteinuria-Glomerular proteinuria-
 Excretion of more than 2 g/24hrs urine isExcretion of more than 2 g/24hrs urine is
indication of glomerular disease likely, andindication of glomerular disease likely, and
also a indication of possible renal biopsy.also a indication of possible renal biopsy.
Eg.Eg.
 GlomerulonephritisGlomerulonephritis
 Lupus nephritisLupus nephritis

10. Classification Of ProteinuriaClassification Of Proteinuria
 Tubular proteinuria-Tubular proteinuria- is the presence ofis the presence of
large amount of small proteins, hardlylarge amount of small proteins, hardly
exceeds 1.5g/24hr urine, maximum PCRexceeds 1.5g/24hr urine, maximum PCR
150-200 mg/mmol, while the serum150-200 mg/mmol, while the serum
proteins have normal concentrations. Eg-proteins have normal concentrations. Eg-
 Interstitial nephritis, Falconi’s syndromeInterstitial nephritis, Falconi’s syndrome
 Drugs- NSAIDS, ciclosporin, contrastDrugs- NSAIDS, ciclosporin, contrast
mediamedia
 ARF, Acute hypersensitivityARF, Acute hypersensitivity
 Hypertensive nephrosclerosisHypertensive nephrosclerosis

11. Classification Of ProteinuriaClassification Of Proteinuria
• Prerenal Proteinuria:Prerenal Proteinuria: The increasedThe increased
concentration of small proteins in theconcentration of small proteins in the
plasma, which can be filtered in theplasma, which can be filtered in the
glomerulus, leads to an increased proteinglomerulus, leads to an increased protein
concentration in the primary urine andconcentration in the primary urine and
failure of the complete reabsorption by thefailure of the complete reabsorption by the
tubular cellstubular cells. Eg-. Eg-
• Bence Jonce proteinuria in multiple myelomaBence Jonce proteinuria in multiple myeloma
oror Non-Hodgkin lymphomaNon-Hodgkin lymphoma
• RhabdomyolysisRhabdomyolysis
• HemolysisHemolysis

12. Classification Of ProteinuriaClassification Of Proteinuria
 Postrenal proteinuria:Postrenal proteinuria:
Proteinuria due to bleeding or infection ofProteinuria due to bleeding or infection of
the kidneys, ureter, bladder or urethra isthe kidneys, ureter, bladder or urethra is
called postrenal proteinuria.called postrenal proteinuria. Eg-Eg-
 HematuriaHematuria
 Infection in kidneyInfection in kidney, ureter, bladder or, ureter, bladder or
urethraurethra
 Vaginal dischargeVaginal discharge
 MenstruationMenstruation

13. Selectivity of ProteinuriaSelectivity of Proteinuria
• It is a relative glomerular selectivity for proteins,It is a relative glomerular selectivity for proteins,
although it is of little significancealthough it is of little significance
• It is the ratio of clearance of larger molecule withIt is the ratio of clearance of larger molecule with
that of smaller i.e., IgG, IgM against that ofthat of smaller i.e., IgG, IgM against that of
albuminalbumin
– >20% to that of albumin, represents nonselective>20% to that of albumin, represents nonselective
proteinuriaproteinuria
– <10%is highly selective<10%is highly selective
– 10 %to 20% is of little discriminatory value10 %to 20% is of little discriminatory value
• This is of little importance ,except to distinguishThis is of little importance ,except to distinguish
between minimal change disease from otherbetween minimal change disease from other
forms of nephritis or glomerular diseaseforms of nephritis or glomerular disease

14. Selective Glomerular Proteinuria:Selective Glomerular Proteinuria:
 Selective glomerular proteinuria is theSelective glomerular proteinuria is the
increased excretion of more than 300 mgincreased excretion of more than 300 mg
medium-sized negatively charged proteinsmedium-sized negatively charged proteins
such as albumin in a 24-h urinesuch as albumin in a 24-h urine
collection.eg-collection.eg-
 Minimal-change GN)Minimal-change GN)
 IgA-nephropathyIgA-nephropathy
 EPH-gestosisEPH-gestosis
 Lupus nephritis with low activityLupus nephritis with low activity

15. Non-Selective Glomerular Proteinuria:Non-Selective Glomerular Proteinuria:
 Non-selective glomerular proteinuria is theNon-selective glomerular proteinuria is the
increased excretion of more than 3000 mgincreased excretion of more than 3000 mg
proteins of any size in a 24-h urine collection.proteins of any size in a 24-h urine collection.
Eg-Eg-
 GlomerulonephritisGlomerulonephritis
 Lupus nephritisLupus nephritis
 EPH-gestosisEPH-gestosis
 AmyloidosisAmyloidosis

16. EVALUATION OF THEEVALUATION OF THE
PATIENT WITH PROTEINURIAPATIENT WITH PROTEINURIA

17. Clinical EvaluationClinical Evaluation
HistoryHistory
 Onset: acuity, durationOnset: acuity, duration
 Diabetic history if applicable, esp. h/oDiabetic history if applicable, esp. h/o
retinopathy/neuropathyretinopathy/neuropathy
 Renal symps: edema, HTN, hematuria,Renal symps: edema, HTN, hematuria,
foamy urinefoamy urine
 Constitutional symps: fever, nausea,Constitutional symps: fever, nausea,
appetite, weight changeappetite, weight change
 Symps of coagulopathy: DVT/P.E.Symps of coagulopathy: DVT/P.E.

18. Clinical EvaluationClinical Evaluation
History (cont.)History (cont.)
 Rheumatological ROSRheumatological ROS
 Malignancy ROSMalignancy ROS
 Medications including OTC and herbalsMedications including OTC and herbals
 Family hx of renal diseaseFamily hx of renal disease
 Exposure to toxinsExposure to toxins

19. Clinical EvaluationClinical Evaluation
Physical ExaminationPhysical Examination
 General examinations- BP and weight,General examinations- BP and weight,
edema, rashesedema, rashes
 Systemic examinations includingSystemic examinations including
cardiopulmonary and musculoskeletalcardiopulmonary and musculoskeletal
systemsystem
 Fundoscopic examFundoscopic exam

20. Clinical EvaluationClinical Evaluation
Labs and StudiesLabs and Studies
 Required: CBC, Urine R/E, 24-hr urine orRequired: CBC, Urine R/E, 24-hr urine or
spot urine for protein/creatinine, Urinespot urine for protein/creatinine, Urine
dipstick testdipstick test
 As clinically indicated:, fasting lipid panel,As clinically indicated:, fasting lipid panel,
HbA1c, ANA, C3/C4, hepatitis B/C,HbA1c, ANA, C3/C4, hepatitis B/C,
ophthalmology exam, renal ultrasound +/-ophthalmology exam, renal ultrasound +/-
SPEP/UPEPSPEP/UPEP
 Renal biopsy as indicatedRenal biopsy as indicated

21. Clinical EvaluationClinical Evaluation
Urine dipstickUrine dipstick
• Dipstick analysis is used in most patients in out doorDipstick analysis is used in most patients in out door
settingsetting
• False positive resultsFalse positive results
– Alkaline urine (pH>7.5)Alkaline urine (pH>7.5)
– When dipstick is immersed too longWhen dipstick is immersed too long
– With highly concentrated urineWith highly concentrated urine
– With gross hematuriaWith gross hematuria
– In presence of penicillins, sulfonamide or tolbutamideIn presence of penicillins, sulfonamide or tolbutamide
– With pus, semen or vaginal secretionsWith pus, semen or vaginal secretions
• False negative resultsFalse negative results
– Dilute urine (sp. gravity >1.015)Dilute urine (sp. gravity >1.015)
– Urinary protein are of low molecular weightUrinary protein are of low molecular weight

22. Clinical EvaluationClinical Evaluation
Quantitation of ProteinuriaQuantitation of Proteinuria
 24-hr urine is gold standard, however is24-hr urine is gold standard, however is
often not easily obtained.often not easily obtained.
 Spot urine protein/creatinine ratio isSpot urine protein/creatinine ratio is
easier to get, nearly as accurate.easier to get, nearly as accurate.
 ALWAYS GET A CREATININE WITHALWAYS GET A CREATININE WITH
ANY QUANTITATIVE MEASURE OFANY QUANTITATIVE MEASURE OF
URINE!URINE!

23. Clinical EvaluationClinical Evaluation
Quantitation of ProteinuriaQuantitation of Proteinuria
Spot Urinary Protein To Creatinine RatioSpot Urinary Protein To Creatinine Ratio
(Upr/Cr)(Upr/Cr)
• It is an alternative to 24-hr urine protein estimationIt is an alternative to 24-hr urine protein estimation
• Correlation between UPr/Cr ratio has beenCorrelation between UPr/Cr ratio has been
demonstrated in various diseases like diabetesdemonstrated in various diseases like diabetes
mellitus, pre-ecclampsia, rheumatic diseasemellitus, pre-ecclampsia, rheumatic disease
• Normal value is < 0.2 which corresponds toNormal value is < 0.2 which corresponds to
proteinuria < 200 mg/24hrsproteinuria < 200 mg/24hrs
• Benefit of it is-Benefit of it is-
01.Ease of collection.01.Ease of collection.
02. Lack of error from over & under collection02. Lack of error from over & under collection

24. Urine microscopic analysisUrine microscopic analysis
 When proteinuria is found on a dipstick analysis, the urinaryWhen proteinuria is found on a dipstick analysis, the urinary
sediment should be examined microscopically for-sediment should be examined microscopically for-
Fatty casts, free fat or oval fat bodies Nephrotic range proteinuria (>3.5 g /24
hours)
Leukocytes, leukocyte casts with bacteria Urinary tract infection
Leukocytes, leukocyte casts without bacteria Renal interstitial disease
Normal-shaped erythrocytes Suggestive of lower urinary tract lesion
Dysmorphic erythrocytes Suggestive of upper urinary tract lesion
Erythrocyte casts Glomerular disease
Waxy, granular or cellular casts Advanced chronic renal disease
Eosinophiluria Drug-induced acute interstitial nephritis
Hyaline casts No renal disease; present with dehydration

25. SELECTED INVESTIGATIONS TO BE CONSIDERED IN PROTEINURIA
TEST INTERPRETATION
Antinuclear Antibody Elevated in SLE
Antistreptolysin O Titre Elevated after streptococcal GN
Complement C3 & C4 Levels low in RPGN
ESR If normal help to rule out infection or inflammation
Fasting Blood sugar Elevated in Diabetes Mellitus
Hemoglobin, Hct Low in CRF
HIV, VDRL & Hepatitis serology All are associated with glomerular proteinuria
S. Electrolytes( Na+
, K+
) Screening for any abnormalities consequent to renal
disease
Serum & Urine protein
Electrophoresis
Abnormal in multiple myeloma
Serum Urate Elevated urates can lead to tubulointerstitial disease
and stones
USG KUB For structural renal disease
Chest X Ray Systemic diseases like sarcoidosis

26. Clinical EvaluationClinical Evaluation
When to Refer to NephrologyWhen to Refer to Nephrology
 Option 1: refer everybody.Option 1: refer everybody.
 Option 2: refer patients after evaluationOption 2: refer patients after evaluation
for transient and orthostatic proteinuriafor transient and orthostatic proteinuria
(unless underlying systemic disease).(unless underlying systemic disease).
Diabetics referred at time ofDiabetics referred at time of
microalbuminuria.microalbuminuria.

27. Evaluation of transientEvaluation of transient
proteinuriaproteinuria
 If results of microscopic analysis areIf results of microscopic analysis are
inconclusive and the dipstick analysisinconclusive and the dipstick analysis
shows trace to 2+protein, the dipstick testshows trace to 2+protein, the dipstick test
should be repeated on morning specimenshould be repeated on morning specimen
at least twice during next monthat least twice during next month
 If subsequent dipstick test are negative theIf subsequent dipstick test are negative the
patient has transient proteinuriapatient has transient proteinuria
 No subsequent F/U needed.No subsequent F/U needed.

28. Evaluation of OrthostaticEvaluation of Orthostatic
proteiuriaproteiuria
• Persons younger than 30 yrs who excretePersons younger than 30 yrs who excrete
<2gm of protein /day with normal creatinine<2gm of protein /day with normal creatinine
clearance should be tested for orthostatic orclearance should be tested for orthostatic or
postural proteinuriapostural proteinuria
• This benign condition occur in 3 to 5 %ofThis benign condition occur in 3 to 5 %of
adolescent and young adults, it isadolescent and young adults, it is
characterized by increased protein excretioncharacterized by increased protein excretion
in upright position but normal excretion inin upright position but normal excretion in
supinesupine
• Annual blood pressure measurement isAnnual blood pressure measurement is
recommended in these patientsrecommended in these patients

29. Evaluation of IsolatedEvaluation of Isolated
ProteinuriaProteinuria
 A proteinuric patient with normal renal function,A proteinuric patient with normal renal function,
no evidence of systemic disease, normal urinaryno evidence of systemic disease, normal urinary
sediments and normal blood pressure is consideredsediments and normal blood pressure is considered
to have isolated proteinuriato have isolated proteinuria
 Protein excretion is usually <2 gm/dayProtein excretion is usually <2 gm/day
 This pts should be followed with blood pressureThis pts should be followed with blood pressure
measurement, urinalysis and creatinine clearancemeasurement, urinalysis and creatinine clearance
every 6 month .every 6 month .

30. Evaluation of PersistentEvaluation of Persistent
ProteinuriaProteinuria
• When diagnosis of persistent proteinuria isWhen diagnosis of persistent proteinuria is
established, a detailed history and physicalestablished, a detailed history and physical
examination should be performed, looking forexamination should be performed, looking for
systemic disease with renal involvementsystemic disease with renal involvement
• An adult with proteinuria >2gm /24 hr requiresAn adult with proteinuria >2gm /24 hr requires
aggressive work upaggressive work up
• If there is decreased creatinine clearance or anIf there is decreased creatinine clearance or an
unclear cause, further investigations should beunclear cause, further investigations should be
done in consultation with nephrologistdone in consultation with nephrologist

31. E v a lu a t io n o f P r o t e in u r ia
T r a n s i e n t :
P e r i o d ic
r e a s s e s s m e n t
R e a s s u r a n c e ,
P e r i o d ic
R e a s s e s s m e n t
O r t h o s t a t ic
F u r t h e r e v a l u a t i o n
( R e n a l u lt r a s o u n d ,
N e p r h o l o g y
R e f e r r a l )
F i x e d
P e r s is t e n t
T r a n s i e n t o r
p e r s i s t e n t ?
( C o n f i r m o n
2 4 h r u r i n e o r s p o t r a t io
D i p s t i c k p o s i t i v e
S S A n e g a t i v e
O v e r f l o w
p r o t e i n u r ia
( L i g h t c h a i n s ,
l y s o z y m u r i a , e t c
S S A p o s i t i v e
b u t d i p s t i c k n e g a t i v e
o r d i s p r o p o r t i o n a t e ly
s m a l l
A s s e s s m e n t o f
P r o t e i n u r ia

32. Algoridom of persistantAlgoridom of persistant
proteinuriaproteinuria

33. Clinical EvaluationClinical Evaluation
Who To BiopsyWho To Biopsy
• Non-diabetic nephrotic syndrome or glomerularNon-diabetic nephrotic syndrome or glomerular
proteinuriaproteinuria
• Isolated proteinuria with renal characteristicsIsolated proteinuria with renal characteristics
• Nephrotic syndrome in children not respondingNephrotic syndrome in children not responding
to steroidsto steroids
• SLE for classificationSLE for classification
• Planned use of immunosuppressive agents inPlanned use of immunosuppressive agents in
primary GNs (renal insufficiency, severe edema,primary GNs (renal insufficiency, severe edema,
hypertension)hypertension)
• Diagnosis of plasma cell dyscrasiasDiagnosis of plasma cell dyscrasias

34. MANAGEMENT OFMANAGEMENT OF
PROTEINURIAPROTEINURIA

35. ManagementManagement
Blood Pressure ControlBlood Pressure Control
 Diabetics: control of BP shown to slowDiabetics: control of BP shown to slow
progression of nephropathy in severalprogression of nephropathy in several
studies.studies.
 Non-diabetics: BP control to MAP < 92 vs.Non-diabetics: BP control to MAP < 92 vs.
107 associated with less progression of107 associated with less progression of
disease. Benefit greatest in nephroticdisease. Benefit greatest in nephrotic
patients.patients.

36. ManagementManagement
ACEI and ARBSACEI and ARBS
 ACEI or ARB are first line drugs.ACEI or ARB are first line drugs.
 Type I Diabetes: Captopril use associatedType I Diabetes: Captopril use associated
with slower progression, less proteinuriawith slower progression, less proteinuria
without or without co-existing HTN (Lewiswithout or without co-existing HTN (Lewis
et alet al, 1993, Viberti et al, 1994), 1993, Viberti et al, 1994)
 Type II Diabetes: Enalapril use associatedType II Diabetes: Enalapril use associated
with slower progression, less proteinuria.with slower progression, less proteinuria.
(Ravid(Ravid et alet al, 1993, 1996)., 1993, 1996).

37. ManagementManagement
ACE InhibitorsACE Inhibitors
• Nondiabetic disease: use of benazeprilNondiabetic disease: use of benazepril
reduced by 38% the 3-yr progression ofreduced by 38% the 3-yr progression of
renal failure in various diseases.renal failure in various diseases.
Reduction greater with higher proteinuriaReduction greater with higher proteinuria
(Maschio(Maschio et alet al, 1996)., 1996).
• Similar data emerging for angiotensin IISimilar data emerging for angiotensin II
receptor antagonists.receptor antagonists.
• Some meta analysis shows that nonSome meta analysis shows that non
dihyropiridine Ca channel blockers havedihyropiridine Ca channel blockers have
anti proteinuric effect.anti proteinuric effect.

38. ManagementManagement
Non-specific TreatmentNon-specific Treatment
 BP control: <130/80 for bothBP control: <130/80 for both
nondiabetics, and diabetics.nondiabetics, and diabetics.
 Lipid control: TChol < 200, LDL < 100Lipid control: TChol < 200, LDL < 100
with HMG Co-A reductase inhibitors.with HMG Co-A reductase inhibitors.
 Glycemic control for diabetics: Hb A1C <Glycemic control for diabetics: Hb A1C <
7%.7%.

39. ManagementManagement
TreatmentTreatment
 Moderate dietary protein restriction: 0.8Moderate dietary protein restriction: 0.8
mg/kg/day + urine protein losses, carefulmg/kg/day + urine protein losses, careful
monitoring of nutritional status.monitoring of nutritional status.
 Edema: diuretics, sodium restrictionEdema: diuretics, sodium restriction
 Specific immunosuppressive therapies forSpecific immunosuppressive therapies for
primary glomerular diseases as indicated.primary glomerular diseases as indicated.

40. PrognosisPrognosis
 Diabetic nephropathy: progression toDiabetic nephropathy: progression to
ESRD over 10-20 years after onset ofESRD over 10-20 years after onset of
proteinuria.proteinuria.
 Isolated non-nephrotic proteinuria: 20-yrIsolated non-nephrotic proteinuria: 20-yr
follow-up shows incidence ~40% renalfollow-up shows incidence ~40% renal
insufficiency, ~50% HTN.insufficiency, ~50% HTN.
 Nephrotic syndrome: variable but poorerNephrotic syndrome: variable but poorer
overall prognosis.overall prognosis.

41. THANK YOUTHANK YOU