Dr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFC

Fellowship in Intensive Care MedicineFellowship in Intensive Care Medicine

Infection Control Fellows Course Infection Control Fellows Course

Consultant Internal Medicine and Critical CareConsultant Internal Medicine and Critical Care

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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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