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Dr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFC
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References:References:1.1. Brenner’s & Rector’s The Kidney 7Brenner’s & Rector’s The Kidney 7thth Ed. Ed.2.2. Harrison’s Internal Medicine 17Harrison’s Internal Medicine 17thth Ed. Ed.3.3. Oxford Textbook Of Clinical NephrologyOxford Textbook Of Clinical Nephrology4.4. Internet Internet
Proteinuria- How To Proteinuria- How To Approach?Approach?
Problem StatementProblem Statement
Proteinuria is a common finding in at Proteinuria is a common finding in at least 17% adults in general practice, least 17% adults in general practice, in routine dip stick screeningin routine dip stick screening
Fewer than 2% of patients whose Fewer than 2% of patients whose urine dipstick is positive for protein urine dipstick is positive for protein have serious and treatable urinary have serious and treatable urinary tract disorderstract disorders
Definition Definition
240 years ago, Hippocrates noted 240 years ago, Hippocrates noted the association between “Bubbles on the association between “Bubbles on surface of urine” and kidney diseasesurface of urine” and kidney disease
Proteinuria is defined as protein Proteinuria is defined as protein excretion >150mg/day.excretion >150mg/day.
Most of the positive dip stick test Most of the positive dip stick test results are due to benign results are due to benign proteinuria, which has no associated proteinuria, which has no associated morbidity and mortalitymorbidity and mortality
Causes of Benign Causes of Benign ProteinuriaProteinuria
DehydrationDehydration Emotional stressEmotional stress Fever Fever Heat injuryHeat injury Intense physical activityIntense physical activity Most acute illnessesMost acute illnesses Orthostatic (postural )disorderOrthostatic (postural )disorder
70 mg/d
5mg/d
10 mg/d 15 mg/d15 mg/d
35 mg/d
Tamm Horsfall Protein Blood Group Related AntigensAlbumin MucopolysaccaridesHormones and Enzymes Immunoglobulins
Composition Of Urinary Composition Of Urinary ProteinProtein
Mechanism of Mechanism of ProteinuriaProteinuria
FILTRATION OF BLOOD OCCURS IN GLOMERULUSFILTRATION OF BLOOD OCCURS IN GLOMERULUS GLOMERULAR FILTRATION BARRIER CONSISTS OF:GLOMERULAR FILTRATION BARRIER CONSISTS OF:
1. Capillary Endothelium1. Capillary Endothelium 2.Glomerular Basement Membrane2.Glomerular Basement Membrane
3.Visceral Epithelium with foot 3.Visceral Epithelium with foot processes forms slit diaphragm processes forms slit diaphragm
GLOMERULAR FILTRATION BARRIER IS SIZE & GLOMERULAR FILTRATION BARRIER IS SIZE & CHARGE DEPANDENTCHARGE DEPANDENT
CHARGE IS ACCOUNTED BYCHARGE IS ACCOUNTED BY :- Negative charge heparan sulfate present in :- Negative charge heparan sulfate present in
GBMGBM :- Sialoglycoprotein of epithelium & :- Sialoglycoprotein of epithelium &
Endothelium Endothelium cell cell
Mechanism of Mechanism of ProteinuriaProteinuria
SIZE BARRIER IS ACCOUNTED BY:SIZE BARRIER IS ACCOUNTED BY:
Slit diphragm made up of podocytes of Slit diphragm made up of podocytes of visceral epithelium.visceral epithelium.
Hence structure which is negatively charged Hence structure which is negatively charged and large size is restricted by GFBand large size is restricted by GFB
Classification Of Classification Of ProteinuriaProteinuria
01.ACCORDING TO QUANTITY:01.ACCORDING TO QUANTITY:
MILD : < 500 mgMILD : < 500 mg MODERATE : 500 mg -2 gmMODERATE : 500 mg -2 gm SEVERE : > 2 gmSEVERE : > 2 gm
02.ACCORDING TO NATURE:02.ACCORDING TO NATURE: SELECTIVESELECTIVE NON SELECTIVENON SELECTIVE
03.ACCORDING TO SITE03.ACCORDING TO SITE : :
TYPETYPE PATHOPHYSIOLOGIPATHOPHYSIOLOGIC FEATURESC FEATURES CAUSES CAUSES
Glomerular
Increased glomerular capillary permeability to proteins
Primary or secondary glomerulopathy
Tubular
Decreased tubular resorbtion of proteins in glomerular filterate
Tubular or interstitial disease caused by drugs, hypertensive glomerulosclerosis
Overflow Increased production of low molecular weight proteins
Monoclonal gammopahy, leukemia
Causes Of ProteinuriaCauses Of Proteinuria Primary glomerulonephropathy Primary glomerulonephropathy
Minimal change disease Minimal change disease Idiopathic membranous glomerulonephritis Idiopathic membranous glomerulonephritis Focal segmental glomerulonephritis Focal segmental glomerulonephritis Membranoproliferative glomerulonephritis Membranoproliferative glomerulonephritis IgA nephropathy IgA nephropathy
Secondary glomerulonephropathy Secondary glomerulonephropathy Diabetes mellitus Diabetes mellitus Collagen vascular disorders (e.g., lupus nephritis) Collagen vascular disorders (e.g., lupus nephritis) Amyloidosis Amyloidosis Preeclampsia Preeclampsia Infection (e.g., HIV, hepatitis B and C, poststreptococcal illness, Infection (e.g., HIV, hepatitis B and C, poststreptococcal illness,
syphilis, malaria and endocarditis) syphilis, malaria and endocarditis) Gastrointestinal and lung cancers Gastrointestinal and lung cancers Lymphoma, chronic renal transplant rejection Lymphoma, chronic renal transplant rejection
Glomerulonephropathy associated with the following drugs: Glomerulonephropathy associated with the following drugs: Heroin Heroin NSAIDs NSAIDs Gold components Gold components Penicillamine Penicillamine Lithium Lithium Heavy MetalHeavy Metal
Causes Of ProteinuriaCauses Of Proteinuria TubularTubular
Hypertensive nephrosclerosisHypertensive nephrosclerosis Tubulointerstitial disease due to Tubulointerstitial disease due to
Uric acid nephropathyUric acid nephropathy Acute hypersenstivity Acute hypersenstivity Interstitial nephritisInterstitial nephritis Fanconi syndromeFanconi syndrome Heavy metals & DrugsHeavy metals & Drugs Sickle cell diseaseSickle cell disease
OverflowOverflow HemoglobinuriaHemoglobinuria MyoglobinuriaMyoglobinuria Multiple myelomaMultiple myeloma AmyloidosisAmyloidosis
Selectivity of Proteinuria Selectivity of Proteinuria It is a relative glomerular selectivity for It is a relative glomerular selectivity for
proteins, although it is of little significanceproteins, although it is of little significance It is the ratio of clearance of larger molecule It is the ratio of clearance of larger molecule
with that of smaller i.e., IgG, IgM against with that of smaller i.e., IgG, IgM against that of albuminthat of albumin >20% to that of albumin, represents >20% to that of albumin, represents
nonselective proteinurianonselective proteinuria <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 This is of little importance ,except to distinguish between minimal change disease distinguish between minimal change disease from other forms of nephritis or glomerular from other forms of nephritis or glomerular diseasedisease
Method Description Detection limit(mg/l)
Comments
KjeldahlRemove non-protein nitrogen, digest protein, measure protein nitrogen
10–20Reference and research method
Biuret
Copper reagent, measures peptide bonds
50
Requires precipitation of proteins, used for 24-h measurement in some laboratories
Turbidimetric
Addition of trichloracetic or sulfosalicylic acids alters colloid properties and produces turbidity to be read in densitometer. Benzethomecin also used
50–100
Imprecise, different readings for albumin and globulin
Dye-binding
Indicator changes color in presence of protein (e.g. Coomassie brilliant blue)
50–100
Different proteins bind differently; several different dyes in use; used in many laboratories for 24-h excretion
Nephelometric
Specific antialbumin antibody used
Measures albumin excretion not total protein. Does not detect globulins
Stick tests
Impregnated with indicator dye (bromocresol green) which changes color in the presence of protein
100 mg/l
Reacts poorly with globulins. Usual clinical screening test
Negative ( <10 mg /dl )Negative ( <10 mg /dl ) Trace ( 10 to 20mg/dl )Trace ( 10 to 20mg/dl ) 1+ ( 30mg /dl )1+ ( 30mg /dl )
Detecting And Quantifying Detecting And Quantifying ProteinuriaProteinuria
Dipstick analysis is used in most patients in out door setting Dipstick analysis is used in most patients in out door setting False positive results False 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
The resuts are graded as – The resuts are graded as –
The SULFOSALICYLIC ACID (SSA) turbidity test and The SULFOSALICYLIC ACID (SSA) turbidity test and IMMUNOELECTROPHORESIS qualitatively screens for proteinuria IMMUNOELECTROPHORESIS qualitatively screens for proteinuria especially Bence Jones proteinuriaespecially Bence Jones proteinuria
2+ ( 100 mg /dl )2+ ( 100 mg /dl ) 3+ ( 300 mg/dl )3+ ( 300 mg/dl ) 4+ ( >1000mg/dl )4+ ( >1000mg/dl )
Detecting And Quantifying Detecting And Quantifying ProteinuriaProteinuria
As urine dipstick and SSA tests are crude methods and value As urine dipstick and SSA tests are crude methods and value depends upon amount of urine produced, they correlate poorly depends upon amount of urine produced, they correlate poorly with quantitative urine protein determination with quantitative urine protein determination
Patients with persistent proteinuria should undergo 24-hr urine Patients with persistent proteinuria should undergo 24-hr urine protein estimation. The urinary creatinine concentration protein estimation. The urinary creatinine concentration should be included in 24-hr measurement to determine should be included in 24-hr measurement to determine adequacy of specimen (normal excretion in men=16 to adequacy of specimen (normal excretion in men=16 to 26mg/kg/day and in women =12 to24 mg/kg/day as it depend 26mg/kg/day and in women =12 to24 mg/kg/day as it depend on muscle mass)on muscle mass)
24- hr urine should be collected by instructing the patient to 24- hr urine should be collected by instructing the patient to discard first morning void; specimen of all subsequent voiding discard first morning void; specimen of all subsequent voiding should be collected including the first morning sample on should be collected including the first morning sample on second daysecond day
Detecting And Quantifying Detecting And Quantifying ProteinuriaProteinuria
Spot Urinary Protein To Creatinine Ratio (Upr/Cr)Spot Urinary Protein To Creatinine Ratio (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 been Correlation between UPr/Cr ratio has been
demonstrated in various diseases like diabetes demonstrated in various diseases like diabetes mellitus, pre-ecclampsia, rheumatic diseasemellitus, pre-ecclampsia, rheumatic disease
Normal value is < 0.2 which corresponds to Normal 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 collection 02. Lack of error from over & under collection
Diagnostic Evaluation Diagnostic Evaluation When proteinuria is found on a dipstick analysis, the urinary sediment When proteinuria is found on a dipstick analysis, the urinary sediment
should be examined microscopically for-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
RBC Cast
Hyaline cast
Hyaline and granular cast
Coarse granular cast adjacent WBCs
Final coarse granular cast
Oval fat body with adjacent hyaline cast
WBC cast
Transient ProteinuriaTransient Proteinuria
If results of microscopic analysis are If results of microscopic analysis are inconclusive and the dipstick analysis inconclusive and the dipstick analysis shows trace to 2+protein, the dipstick test shows trace to 2+protein, the dipstick test should be repeated on morning specimen should be repeated on morning specimen at least twice during next monthat least twice during next month
If subsequent dipstick test are negative If subsequent dipstick test are negative the patient has transient proteinuriathe patient has transient proteinuria
It is not associated with increased It is not associated with increased mortality or morbidity,and specific follow-mortality or morbidity,and specific follow-up is not required up is not required
Persistent Proteinuria Persistent Proteinuria When diagnosis of persistent proteinuria is When diagnosis of persistent proteinuria is
established, a detailed history and physical established, a detailed history and physical examination should be performed, looking for examination should be performed, looking for systemic disease with renal involvement systemic disease with renal involvement
A medication history is important A medication history is important A 24-hr urine protein or a UPr/Cr ratio on random A 24-hr urine protein or a UPr/Cr ratio on random
urine sample should be obtained urine sample should be obtained An adult with proteinuria >2gm /24 hr requires An adult with proteinuria >2gm /24 hr requires
aggressive work up aggressive work up If creatinine clearance is normal and if diagnosis If creatinine clearance is normal and if diagnosis
is clear as diabetes or uncompensated CHF, treat is clear as diabetes or uncompensated CHF, treat underlying medical condition with regular follow underlying medical condition with regular follow upup
If there is decreased creatinine clearance or an If there is decreased creatinine clearance or an unclear cause, further investigations should be unclear cause, further investigations should be done in consultation with nephrologist done in consultation with nephrologist
Orthostatic Proteinuria Orthostatic Proteinuria Persons younger than 30 yrs who Persons younger than 30 yrs who
excrete <2gm of protein /day with excrete <2gm of protein /day with normal creatinine clearance should be normal creatinine clearance should be tested for orthostatic or postural tested for orthostatic or postural proteinuriaproteinuria
This benign condition occur in 3 to 5 This benign condition occur in 3 to 5 %of adolescent and young adults, it is %of adolescent and young adults, it is characterized by increased protein characterized by increased protein excretion in upright position but excretion in upright position but normal excretion in supinenormal excretion in supine
Diagnosis is made by split urine Diagnosis is made by split urine specimen collection specimen collection
Orthostatic Proteinuria Orthostatic Proteinuria
The first morning void is discarded , a 16 hr The first morning void is discarded , a 16 hr daytime specimen is obtained with patient daytime specimen is obtained with patient performing normal activities and finishing performing normal activities and finishing the collection by voiding before bed time, an the collection by voiding before bed time, an overnight 8 hr. specimen is then collectedovernight 8 hr. specimen is then collected
The day time specimen typically has an The day time specimen typically has an increased concentration of protein, while increased concentration of protein, while night time specimen has having normal night time specimen has having normal concentrationconcentration
It is a benign condition associated with It is a benign condition associated with normal renal function after as long as 20 to normal renal function after as long as 20 to 50 yrs of follow up 50 yrs of follow up
Annual blood pressure measurement is Annual blood pressure measurement is recommended in these patients recommended in these patients
Isolated Proteinuria Isolated Proteinuria A proteinuric patient with normal renal function, A proteinuric patient with normal renal function,
no evidence of systemic disease, normal urinary no evidence of systemic disease, normal urinary sediments and normal blood pressure is sediments and normal blood pressure is considered to have isolated proteinuriaconsidered to have isolated proteinuria
Protein excretion is usually <2 gm/dayProtein excretion is usually <2 gm/day 20%of these patients have risk for renal 20%of these patients have risk for renal
insufficiency after 10years and should be insufficiency after 10years and should be followed with blood pressure measurement, followed with blood pressure measurement, urinalysis and creatinine clearance every 6 urinalysis and creatinine clearance every 6 month month
Isolated proteinuria with excretion >2 gm /day Isolated proteinuria with excretion >2 gm /day usually signifies glomerular disease and needs usually signifies glomerular disease and needs further evaluation.further evaluation.
ALGORITHM FOR EVALUATING
A PATINT WITH PROTEINURIA
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
Microalbuminuria Microalbuminuria It is defined as presence of albumin in urine above It is defined as presence of albumin in urine above
normal range of <30 mg/day but below detectable normal range of <30 mg/day but below detectable range with conventional dipstick methodology range with conventional dipstick methodology i.e.30-299 mg/dayi.e.30-299 mg/day
It is estimated by Radioimmunoassay.It is estimated by Radioimmunoassay. Recent data have established that MA is not only a Recent data have established that MA is not only a
predictor of diabetic complication but also a predictor of diabetic complication but also a powerful independent risk factor of CVDpowerful independent risk factor of CVD
While the contribution of MA as a prognostic While the contribution of MA as a prognostic indicator of cardiovascular events in people with indicator of cardiovascular events in people with diabetes is clear it is still debatable in nondiabetic diabetes is clear it is still debatable in nondiabetic population.population.
Present in Diabetic nephropathy, hypertension, Present in Diabetic nephropathy, hypertension, Cardiac failure & Viral illnessesCardiac failure & Viral illnesses
FINAL COMMENTFINAL COMMENT
A systematic approach to the A systematic approach to the patient with proteinuria will patient with proteinuria will allow the clinician to efficiently allow the clinician to efficiently distinguish between benign and distinguish between benign and pathological causes.pathological causes.
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