Evaluasi dan penanganan

Proteinuria dan Hematuria

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 Specimen Collection

First morning voiding (most concentrated)

Record collection time
Type of specimen (e.g. clean catch)
Analyzed within 2 hours of collection
Free of debris or vaginal secretions

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 Clean Catch

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Specimen Collection
Supra-pubic Needle Aspiration

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Types of Analysis

Macroscopic Examination
Chemical Analysis (Urine Dipstick)
Microscopic Examination
Culture
Cytological Examination

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 Defining Proteinuria

Degree of 24 Hour Urine Urine Dipstick

Proteinuria
Normal <30 mg None
albumin /day
Microalbuminuria 30 300 None
mg/day
Macroalbuminuria 300 3500 >15 mg/dl (trace)
mg/day
Nephrotic Range >3.5 g /day >300 mg/dl (3+)

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Office Urine Dipstick

Trace 15 mg/dl
1+ 30 mg/dl
2+ 100 mg/dl
3+ 300 mg/dl
4+ 2000 mg/dl

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 Urine Dipstick
1+ = 30mg/dL ~ 300mg/day
2+ = 100mg/dL ~ 1g/day
3+ = 300mg/dL ~ 3g/day
4+ = 2000mg/dL ~ 20g/day

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Physiology/Pathophysiology

Protein flow through renal arteries =

121,000 g/day
Protein filtered through glomerulus = 1-2
g/day (< 0.001%)
Protein excreted in urine < 150 mg/day
(<1% of filtered)
Composition of normal urine: Tamm-
Horsfall protein 60-80%, albumin 10-
20%.
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Physiology/Pathophysiology Schematic

1. Filtration
2. Reabsorption/Catabolism

3. Secretion

4. Excretion
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Physiology and Pathophysiology
Etiologies of Proteinuria

Overflow: excess serum concentrations of

protein overwhelm nephrons ability to
reabsorb. Ex.-light chain disease.
Tubular: deficiency reabsorption of proteins
in proximal tubule causing mostly LMW
proteinuria. Exs.-interstitial nephritis,
Fanconis syndrome.
Glomerular: defect causing albuminuria
(>70%) and HMW proteinuria. Exs.-
orthostatic proteinuria, glomerulonephritis.

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DIFFERENTIAL DIAGNOSIS

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Differential Diagnosis
General Categories

Transient proteinuria
Orthostatic proteinuria
Persistent proteinuria

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Differential Diagnosis
Transient Proteinuria

Proteinuria cause by non-renal

causes: fever, exercise, CHF,
seizures.
Resolves when condition resolves.
No further w/u indicated.
Intermittent proteinuria: no clear
etiology, benign condition with
excellent prognosis.
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Differential Diagnosis
Orthostatic Proteinuria

Proteinuria caused by upright position.

Subjects < age 30 with proteinuria < 1.5
g/day.
Diagnosis: split day/night urine
collections. (Or spot protein/creatinine
ratio first AM void and mid afternoon). At
WRAMC, there is an order set called
"Orthostatic Prot" with a picklist

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Differential Diagnosis
Orthostatic Proteinuria

The most important point is the morning

collection, or first AM void spot
protein/creatinine ratio, should be
NORMAL (extrapolating to <150 mg d
over 24 hours, or a ratio of <0.15), not
just lower than the afternoon collection.
Once diagnosis established, excellent
long-term prognosis. Annual follow-up
recommended.
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 Differential Diagnosis
Persistent Proteinuria

Subnephrotic: < 3.5 g/day/1.73 m2 (usually <

2). Nephrotic: > 3.5 g/day/1.73 m2.
Distinction has diagnostic, prognostic, and
therapeutic implications but actual value is
arbitrary.
No practical distinction between nephrotic
syndrome and nephrotic-range proteinuria.

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Differential Diagnosis
Subnephrotic Proteinuria

Transient or orthostatic proteinuria

Hypertensive nephrosclerosis
Ischemic renal disease/renal artery
stenosis
Interstitial nephritis
All causes of nephrotic-range
proteinuria
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Differential Diagnosis
Nephrotic Syndrome

Def: nephrotic-range proteinuria,

lipiduria, edema, hypoalbuminemia,
hyperlipidemia.
Implies glomerular origin of proteinuria.
Clinical manifestations: edema,
hypercoagulability, immunosuppression,
malnutrition, +/- hypertension, +/- renal
failure.

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Differential Diagnosis
Nephrotic Syndrome (cont.)

75% have primary glomerular disease

25% have secondary glomerular disease
Medications: NSAIDs, heavy metals, street
heroin, lithium, penicillamine, a-INF
Infections: post-strep, HIV, hepatitis B/C,
malaria, schistosomiasis
Neoplasms: solid tumors, leukemias,
lymphomas, multiple myeloma
Systemic diseases: diabetes mellitus, SLE,
amyloidosis

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Differential Diagnosis
Diabetic Nephropathy

#1 cause of ESRD in the U.S. (~35% of

all ESRD).
~ 40% of all diabetics (type I and II) will
develop nephropathy.
Microalbuminuria (> 30 mg/day)
develops after ~ 5 years. Proteinuria
after 11-20 years. Progression to ESRD
~15-30 years.

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EVALUATION OF THE PATIENT
WITH PROTEINURIA

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Clinical Evaluation
History

Onset: acuity, duration

Diabetic history if applicable, esp. h/o
retinopathy/neuropathy
Renal ROS: edema, HTN, hematuria,
foamy urine, renal failure
Constitutional sxs: fever, nausea,
appetite, weight change
Sxs of coagulopathy: DVT/RVT/P.E.

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Clinical Evaluation
History (cont.)

Rheumatological ROS
Malignancy ROS
Medications including OTC and herbals
Family hx of renal disease
Exposure to toxins

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Clinical Evaluation
Physical Examination

BP and weight
Fundoscopic exam
Cardiopulmonary exam
Rashes
Edema

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Clinical Evaluation
Labs and Studies

Required: CBC, U/A, 24-hr urine or spot

urine for protein/creatinine
As clinically indicated: lipid panel,
glycosylated Hg, ANA, C3/C4, urine
eosinophils, hepatitis B/C,
ophthalmology exam, renal ultrasound
+/- Doppler study of veins
Renal biopsy as indicated

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 Clinical Evaluation
Urine dipstick

Most sensitive to albumin, least sensitive to

LWM proteins.
Sensitivity ~ 10 mg/dL (~ 300 mg/day).
Coefficient of variability high.
False negatives: small and positively-charged
proteins (light chains), dilute urine.
False positives: radiocontrast dye, Pyridium,
antiseptics, pH > 8.0, gross hematuria.

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Chemical Analysis
Urine Dipstick

Glucose
Bilirubin
Ketones
Specific Gravity
Blood
pH
Protein
Urobilinogen
Nitrite
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Proteinuria

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The Urine Dipstick:
Protein

Chemical Principle
Protein Error of Indicators Method
Negative Pr
H Pr
H Pr
Trace H
Pr Pr
+ (30 mg/dL) H H
H Pr
++ (100 mg/dL) Tetrabromphenol Blue +
H+ H H
+
(buffered to pH 3.0)
H + +
+++ (300 mg/dL) Pr Pr H+ H
Pr
Pr Pr
++++ (2000 mg/dL) Pr
Read at 60 seconds
RR: Negative
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 Causes of Proteinuria

Functional Renal
- Severe muscular exertion - Glomerulonephritis
- Pregnancy - Nephrotic syndrome
- Orthostatic proteinuria - Renal tumor or infection

Pre-Renal Post-Renal
- Fever - Cystitis
- Renal hypoxia - Urethritis or prostatitis
- Hypertension - Contamination with vaginal
secretions
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 Nephrotic Syndrome (> 3.5 g/dL in 24 h)

Primary
- Lipoid nephrosis (severe)
- Membranous glomerulonephritis
- Membranoproliferative glomerulonephritis

Secondary
- Diabetes mellitus (Kimmelsteil-Wilson lesions)
- Systemic lupus erythematosus
- Amyloidosis and other infiltrative diseases
- Renal vein thrombosis

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 Uses and Limitations of Urine Protein Detection

Significance
- Proteinuria and the nephrotic syndrome.

Limitations
- Interference: highly alkaline urine.
- Much more sensitive to albumin than other proteins
(e.g., immunoglobulin light chains).

Other Tests
- Sulfosalicylic acid (SSA) turbidity test.
- Urine protein electrophoresis (UPEP)
- Bence Jones protein

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 Proteins in Normal Urine

Protein % of Total Daily Maximum

Albumin 40% 60 mg
Tamm-Horsfall 40% 60 mg
Immunoglobulins 12% 24 mg
Secretory IgA 3% 6 mg
Other 5% 10 mg

TOTAL 100% 150 mg

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MANAGEMENT OF PROTEINURIA

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Management
Specific vs. Nonspecific Therapies

Proteinuria is not just a marker of kidney

disease, but also a culprit in its
progression.
Control of proteinuria is seen to
ameliorate or arrest glomerular disease
independent of the underlying etiology.
Treatment of secondary causes is
treatment of the underlying disorder plus
supportive care.
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Management
Specific vs. Nonspecific Therapies

Specific therapies on primary

glomerulonephritis depending on
diagnosis: glycemic control,
immunosuppresive agents
(corticosteroids, cyclophosphamide,
chlorambucil, cyclosporine A, fish oil)
Nonspecific therapies independent of
diagnosis: blood pressure and metabolic
control and toward supportive care.
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Management
Blood Pressure Control

Diabetes: control of BP shown to slow

progression of nephropathy in several
studies.
Non-diabetics: BP control to MAP < 92
vs. 107 associated with less progression
of disease. Benefit greatest in nephrotic
patients.
Gains in stroke and heart disease due to
BP control have not been seen in renal
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Management
ACE Inhibitors

Have benefit over and above blood

pressure control.
Type I Diabetes: Captopril use
associated with slower progression, less
proteinuria without or without co-existing
HTN (Lewis et al, 1993, Viberti et al,
1994)
Type II Diabetes: Enalapril use
associated with slower progression, less
proteinuria. (Ravid
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Management
ACE Inhibitors

Nondiabetic disease: use of benazepril

vs. placebo reduced by 38% the 3-yr
progression of renal failure in various
diseases. Reduction greater with higher
proteinuria (Maschio et al, 1996).
Similar data emerging for angiotensin II
receptor antagonists.

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Management
Calcium-Channel Blockers

No benefit with nondihydropyridine

agents.
Diabetes: meta-analysis suggests Non-
dihydropyridine blockers may have
antiproteinuric effect (Gansevoort et al,
1995).
Would recommend as second-line agent
behind ACE inhibitors.

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Management
Lipid Control

Hypoalbuminemia caused increased

lipoprotein synthesis by the liver.
May increase cardiovascular
morbidity/mortality.
Diabetes: small trial suggests that use
of lovastatin has beneficial effect on rate
of renal progression (Lam et al., 1995).

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Management
Glycemic Control

Type I diabetes: intensive glucose

control (HbA1c < 7%) reduced
microalbuminuria by 39% and frank
albuminuria by 54% (DCCT Study,
1993).
Type II diabetes: studies underway.

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Management
Dietary Protein Restriction

Experimental data suggests reduced

metabolic load slows progression of
disease.
Clinical data is underwhelming (MDRD:
no benefit seen except in secondary
analysis).
Probably at most, a small benefit exists.
Must balance potential benefit of protein
restriction with nutritional status.
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Management
Supportive Care

Edema: Cause of significant morbidity.

Rx--diuretics, sodium restriction.
Thromboembolism in nephrotic
syndrome: RVT ~35% incidence, other
complications ~20% incidence.
Prophylactic anticoagulation not
recommended.
Infection: may have low Ig levels,
defective cell-mediated immunity.
Consider Pneumovax.
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RECOMMENDATIONS

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Recommendations
Evaluation

R/O transient and orthostatic proteinuria.

Clinical evaluation for systemic diseases,
medications, infections, and
malignancies as causes of secondary
glomerular disease.
Diabetics: regular screening for
microalbuminuria, early use of ACE
inhibitors, early referral to nephrology.

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Recommendations
Non-specific Treatment

BP control: < 130/80 for nondiabetics, <

125/75 for diabetics.
Maximization of ACE inhibitors/AII receptor
antagonists and non-dihydropyridine calcium-
channel blockers as tolerated.
Lipid control: TChol < 200, LDL < 100 with
HMG Co-A reductase inhibitors.
Glycemic control for diabetics: A1C < 7%.

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Recommendations
Treatment

Moderate dietary protein restriction: 0.8

mg/kg/day + urine protein losses, careful
monitoring of nutritional status.
Edema: diuretics, sodium restriction
Specific immunosuppressive therapies
for primary glomerular diseases as
indicated.

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TAKE HOME MESSAGE

DONT LET
PERSISTENT
PROTEINURIA GO
UNQUANTIFIED OR
UNEVALUATED!
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HEMATURIA

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 DEFINITION
More than three red blood cells are found in
centrifuged urine per high-power field
microscopy
( > 3 RBC/HP).

Normal urine:
no red blood cell or less than three red blood
cell

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 According to the amount of RBC in the
urine, hematuria can be classified as:

microscopic hematuria:

normal colour with eyes

gross hematuria:

tea-colored, cola-colored, pink or

even red

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ETIOLOGY

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 Major causes of hematuria by age and duration

Schematic representation of the major causes of hematuria in relation to the age at which they usually
occur (horizontal axis), transience or persistence (vertical axis), and frequency (blue implies more
frequent).
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 ETIOLOGY
Diseases of the urinary systemthe most
common cause
Vascular
arteriovenous malformation
arterial emboli or thrombosis
arteriovenous fistular
nutcracker syndrome
renal vein thrombosis
loin-pain hematuria syndrom
cogulation abnormality
excessive anticogulation
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Glomerular
IgA nehropathy
thin basement membrane disease (incl.Alport syndrome)
other causes of primary and secondary glomerulonephritis

Interstitial
allergic interstitial nephritis
analgesic nephropathy
renal cystic diseases
acute pyelonephritis
tuberculosis
renal allograft rejection

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Uroepithelium
malignancy
vigorous excise
trauma
papillary necrosis
cystitis/urethritis/prostatitis(usually caused by infection)
parasitic diseases (e.g. schistosomiasis)
nephrolithiasis or bladder calculi

Multiple sites or source unknown

hypercalciuria
hyperuricosuria

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 System disorders
a. Hematological disorders
aplastic anemia leukemia
allergic purpura hemophilia
ITP (idiopathy thrombocytopenic purpura)

b. Infection
infective endocarditis
septicemia
epidemic hemorrhagic fever (Hantaan virus)
scarlet fever (-hemolytic streptococcus)
leptospirosis (leptospire)
filariasis (Wuchereria bancrofti, Brugia malayi)
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c. Connective tissue diseases
systemic lupus erythematosus (SLE)
polyarteritis nodosa

d. Cariovascular diseases
hypertensive nephropathy
chronic heart failure
renal artery sclerosis

e. Endocrine and metabolism diseases

gout
diabetes mellitus

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 Diseases of adjacent organs to urinary
tract
appendicitis salpingitis
carcinoma of the rectum
carcinoma of the colon
uterocervical cancer

Drug and chemical agents

sulfanilamides anticogulation
cyclophosphamide mannitol

miscellaneous
exercise idopathic hematuria

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CLINICAL FEATURE

Color
depends on the amount of red blood
cell in the urine and the pH (see slide
4)
normal: light yellow, pH 6.5
pH
acidic: more darker (brown or black)
alkaline: red
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DIFFERENTIAL DIAGNOSIS

Polluted urine: menstruation

Drug and food: phenosulfonphtha lein (PSP),uric

acid, vegetable
Porphyrism: porphyrin in urine (+)

Hemoglobinuria

hemolysis
soy-like, very few RBC under the microscopy
occult blood test (+)

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 HEMOGLOBINURIA
RBC abnormality
Defects of RBC membrane structure and function
(hereditary spherocytosis)
Deficiency of enzymes (favism)

Hemoglobinopathy (thalassemia)

PNH

Mechanical factor (artificial heart valve), infection

or mismatched blood transfusion

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 LABORATORY TESTS
Three-glass test
Method: collecting the three stages of urine of
a patient during micturition
Result:
the initial specimen containing RBCthe urethra
the last specimen containing RBCthe bladder
neck and trianglar area, posturethra
all the specimens containing RBCupper urinary
tract, bladder

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 Phase-contrast microscopy

to distinguish glomerular from post

glomerular bleeding

post glomerular bleeding: normal size and

shape of RBC
glomerular bleeding: dysmorphic RBC
(acanthocyte)

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 ACCOMPANIED SYMPTOMS

Hematuria with renal colic

renal stone, ureter stone
if with dysuria, miction pause or staining to void: bladder
or urethra stone
Hematuria with urinary frequency,urgency and
dysuria
bladder or lower urinary tract (tuberculosis or tumor)
if accompanied by high spiking fever, chill and loin pain:
pyelonephritis

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 Hematuria with edema and hypertension
glomerulonephritis
hypertensive nephropathy
Hematuria with mass in the kidney
neoplasm
hereditary polycystic kidney
Hematuria with hemorrhage in skin and
mucosa
hematological disorders
infectious diseases
Hematuria with chyluria
filariasis

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 HEMATURIA --Approaching to the patient
(Harrisons Principle of Internal
Medicine,14th Ed)
proteinuria (>500mg/24h)
(-) Dysmorphic RBC or RBC casts
(+)
(+)
Pyuria,WBC casts urine culture
eosinophils
(-) serologic and hematologic
evaluation: blood culture,
Hb electrophoresis, urine cytology, anti-GBM Ab, ANCA,
UA of family member, 24h urinary complement, cryoglobulin
calcium/uric acid HBV,HCV,VDRL,HIV,
(-) As indicated: ASLO
(+)
IVP+/-renal retrograde
ultrasound pyelography or
renal biopsy
(-) arteriogram of cyst
(+) aspiration
cystoscopy
(-) biopsy
CT scan (+) ANCA:antineutrophil cytoplasmic
antibody, VDRL:venereal dis. research
(-) open renal biopsy
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laboratory, ASLO: antisteptolysin O,
follow IVP: intravenous pyelography
Haematuria

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The Urine Dipstick:
Blood

Negative
Chemical Principle
Trace (non-hemolyzed)
Lysing agent to lyse red blood cells

Moderate (non-hemolyzed)
Diisopropylbenzene dihydroperoxide +
Tetramethylbenzidine
Trace (hemolyzed)
Heme
------------> Colored Complex
+ (weak)

++ (moderate) Read at 60 seconds

RR: Negative
Analytic Sensitivity: 10 RBCs
+++ (strong)

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Uses and Limitations of Urine Blood Detection

Significance
- Hematuria (nephritis, trauma, etc)
- Hemoglobinuria (hemolysis, etc)
- Myoglobinuria (rhabdomyolysis, etc)

Limitations
- Interference: reducing agents, microbial peroxidases
- Cannot distinguish between the above disease processes

Other Tests
- Urine microscopic examination
- Urine cytology

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Terima
Kasih

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