DR.Sh.Sajjadieh
nephrologist
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Abnormal quantity of protein excretion in the
urine is called proteinuria.
95% of normal adults excrete less than 150
mg/d.
Children and adolescent can excrete up to 250
mg/d.
Higher rates of protein excretion that persist
beyond a single measurement should be
evaluated.
3
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Proteinuria is defined as urinary protein
excretion exceeding 2 SD from the mean.
Normal values depend upon the age
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Premature neonates
full term neonates
Children <10 yr
Children 10-18 yr
Adults
 140 mg/m2/d
 70 mg/m2/d
 150 mg/d
 300 mg/d
 150 mg/d
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30 to 150 mg/day
Usually only small proteins (<20,000
daltons) pass across capillary wall and
most are reabsorbed in prox. tubules
e.g., a2-microglobulin, apoproteins,
enzymes, peptide hormones
Tamm-Horsfall protein (uromodulin)
 High m. wt. 23 x 106 daltons glycoprotein
 Thick ascending limb and distal convoluted
tubule
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IgA and urokinase in small amounts
 Disruption of glomerular capillary barriers
(high m. wt. proteinuria)
 Tubular damage, inability of prox. tubule to
reabsorb normally filtered proteins (low m.
wt. proteinuria)
 Increased production of normal and abnormal
plasma proteins which are filtered and
inadequately reabsorbed
 Increased tubular production of protein
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PH indicators change color with protein
Sensitive for albumin but not
immunoglobulins
Strongly pigmented urine interferes with
color reaction (hyperbilirubinemia,
pyridium)
False positives in very alkaline urine
Sensitivity, 32-46% using 25 mg/dL
proteinuria
Cold precipitation of proteins with a strong acid urine will become turbid, measured by
photometry
 Poor precision - coefficient of variation is 20%
 Gamma globulins and albumin detected, more
sensitive to the latter
 Substituting trichloracetic acid results in more
sensitivity for gamma globulins
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Turbidity of urine from another
cause
Radiographic contrast dye (high SG
on urinometer but normal dipstick)
Penicillin, cephalosporin,
sulfonamides, tolbutamide, tolectin
False negative in alkaline urine
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If SSA is positive while dipstick reagent is
negative
- non albumin proteinuria is suspected
(e.g., gamma globulin paraproteins)
-Pancreatic transplant patients,
nonalbumin pancreatic enzymes in urine
Radioimmunoassay – double antibody
technique
 Immunoturbidometric technique - albumin +
antibody create a turbid mixture measured by
spectrophotometry
 Albumin - antibody complexes measured by
laser nephelometer
 ELISA
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Urinanalysis
70-80% of excreted protein is in upright
position.
 The urine dipstick for protein primarily
detects albumin.
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15
Urinanalysis
In normal urine, 60% of the proteins
originate from the plasma and other 40%
from the kidney and urogenital tract.
 Normal protein composition is
approximately 40%albumin, 40% TommHorsfal protein, 15% immunoglobulins,
5% other plasma proteins.
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Urinanalysis
Dipstick is simplest and least expensive
method.
 It detects protein concentration > 20 mg%
and depends on urine concentration and is
insensitive to globulin.
 False positive in highly alkaline urine,
presence of bacteria, blood, ammonium
compounds, or chlorhexidine.
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Urinanalysis
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Sulfosalicylic acid is more sensitive (down
to 5 mg%) and react equally with albumin
and globulin.
18
Urinanalysis
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False positive results can occur if the urine
contains tolbutamide, radiocontrast
agents, or high level of cephalosporin,
penicillin, or sulfonamides.
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Urinanalysis
 Quantitatively method is urine
electrophoresis.
 At times, it is necessary to quantify
protein excretion; determining the
24-hour protein collection, or protein
to creatinine ratio.
20
Urinanalysis
Microalbuminuria refers to elevated
urine albumin excretion that is below
the level of detection (30-300 mg/d or
20-200 mg/min) by routine urine
protein dipstick test.
21
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There are three basic types of proteinuria :
glomerular, tubular, and overflow.
Only glomerular proteinuria (ie, albuminuria)
is identified on a urine dipstick.
Glomerular proteinuria :
 the proteinuria in glomerular disease
is due to increased filtration of
macromolecules (such as albumin)
across the glomerular capillary wall.
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Low molecular weight proteins ( such as
microglobulin, immunoglobulin light
chains, retinol-binding protein, and amino
acids) have a molecular weight that is
generally under 25,000 in comparison to
the 69,000 molecular weight of albumin.
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Tubular Proteinuria
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These smaller proteins can be filtered
across the glomerular and are then almost
completely reabsorbed in the proximal
tubule.
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Tubular Proteinuria
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Interference with proximal tubular
reabsorption, due to a variety of
tubulointerstitial diseases or even some
primary glomerular diseases, can lead to
increased excretion of these smaller proteins.
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Tubular proteinuria is not diagnosed clinically
since the dipstick for protein does not detect
low molecular weight proteins and the
quantity excreted is relatively small.
Characteristic
Tubular
Glomerular
Sp. Gravity
Isosthenuric
High (conc.)
Protein
1+ on dipstick
 3+
Hematuria
Usually absent
Often present
Casts
Tubular cells/
none
Variable (RBC,
granular
UPEP
Broad band –
multiple globulin
Albumin peak
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Increased excretion of low molecular weight
proteins can occur with marked overproduction
of a particular protein
(almost always immunoglobulin light chains in
multiple myeloma)
In this setting, the filtered load is increased to a
level that exceeds the normal proximal
reabsorptive capacity.
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Abnormal protein excretion due to tissue or
tumor necrosis.
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Proteinuria without hematuria or an elevated
serum creatinine concentration
asymptomatic and the presence of
proteinuria is discovered incidentally.
This is different from that in patients with
more prominent renal disease who have one
or more of the following: heavy proteinuria
(>3 g/day), lipiduria, edema, and/or an active
urine sediment containing red cells (which
are often dysmorphic) and red cell casts.
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Annual screening for proteinuria is not costeffective in the general population of healthy
individuals under age 60.
Routine urinalysis is recommended for high
risk patients :diabetes or hypertension
Early detection of proteinuria in high risk
patients is important because the
administration of an ACE inhibitor or ARB →
slow the progression of proteinuric chronic
kidney disease.
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Almost all cases of persistent proteinuria are
due to glomerular proteinuria.
Increased filtration of macromolecules (such
as albumin) across the glomerular capillary
wall :
diabetic nephropathy and other glomerular
diseases
orthostatic or exercise-induced proteinuria
Most patients with benign causes of isolated
proteinuria excrete less than 1 to 2 g/day
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Low molecular weight proteins :ß2-microglobulin,
immunoglobulin light chains,, and amino acids — have
a molecular weight that is generally under 25,000 can
be filtered across the glomerulus and are then almost
completely reabsorbed in the proximal tubule.
The increased excretion of immunoglobulin light chains
(or Bence Jones proteins) in tubular proteinuria is mild,
polyclonal (both kappa and lambda), and not injurious to
the kidney. This is in contrast to the monoclonal and
potentially nephrotoxic nature of the light chains in the
overflow proteinuria seen in multiple myeloma.
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Increased excretion of low molecular weight
proteins can occur with marked
overproduction of a particular protein,
leading to increased glomerular filtration and
excretion. This is almost always due to
immunoglobulin light chains in multiple
myeloma, but may also be due to lysozyme
(AML), myoglobin (in rhabdomyolysis), or
hemoglobin (in intravascular hemolysis) .
 Some patients have mixed forms of proteinuria:
 Patients with myeloma kidney also may develop
a component of tubular proteinuria, since the
excreted light chains may be toxic to the
tubules, leading to diminished reabsorption.
 Glomerular diseases such as focal segmental
glomerulosclerosis can be associated with
proximal tubular injury, leading to tubular
proteinuria.
Standard urine dipstick
Detection of albumin via a colorimetric reaction
between albumin and tetrabromophenol blue
producing different shades of green according to the
concentration of albumin in the sample.
 The dipstick is insensitive to the presence of nonalbumin proteins.
 positive dipstick usually reflects glomerular
proteinuria.
 Pure tubular or overflow proteinuria will not be
diagnosed unless a 24-hour urine is collected for some
other reason, or the urine is tested with sulfosalicylic
acid which detects all proteins.
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Both the dipstick and sulfosalicylic acid test
will detect urinary lysozyme (AML). Thus,
lysozyme excretion should be measured in
this setting, particularly if other signs of the
nephrotic syndrome (such as edema and
hyperlipidemia) are absent.
The results with the dipstick and SSA serve as
only a rough guide of the degree of protein
excretion since urine concentration will affect
the measurement.
Determination of the degree of protein
excretion is a central part of the evaluation of
patients with acute and chronic kidney diseases
 The degree of proteinuria is prognostically
important in patients with a primary glomerular
disease.
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Most patients with the benign forms of isolated proteinuria
excrete less than 1 to 2 g/day.
 The degree of proteinuria is used to monitor the
response to therapy.
Most patients with persistent proteinuria
should undergo a quantitative measurement of
protein excretion.
 24-hour urine measurement; however, collecting
these specimens is cumbersome in ambulatory
care settings.
 Random urine specimen to estimate the degree
of proteinuria .This test calculates the total
protein-to-creatinine ratio (mg/g). This ratio
correlates with daily protein excretion expressed
in terms of g per 1.73m2 of body surface area .
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It is important to note the units of
measurement in your laboratory. If the
urinary creatinine concentration is measured
in mmol/L, the formula must be amended as
follows, since 1 mg/dL equals 0.088 mmol/L:
Protein excretion = (Urine
[protein] x 0.088) ÷ Urine [creatinine]
Microalbuminuria is defined as persistent albumin
excretion between 30 and 300 mg/day (20 to 200 µg/min).
 The normal rate of albumin excretion is less than 20
mg/day (15 µg/min).
 The standard urine dipstick is an insensitive method to
detect microalbuminuria, which is the earliest clinical
manifestation of diabetic nephropathy and, in patients
without diabetes, is a marker of increased cardiovascular
risk.
 Dipsticks are available that detect the urine albumin
concentration in this range, but the preferred test for
diagnosis and monitoring is the urine albumin-tocreatinine ratio.
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The urine sediment should be examined for other
signs of glomerular disease such as hematuria, red
cell casts, or lipiduria and Red cell casts.
 If the sediment is unremarkable, the differential
diagnosis includes transient proteinuria, orthostatic
proteinuria, and persistent proteinuria.
 The urine dipstick should be repeated on at least
one other visit. If these subsequent tests are
negative for protein, the likely diagnosis is transient
proteinuria.
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Transient proteinuria is common:
(fever and exercise)
With marked exercise, the excretion of both
albumin and low molecular weight proteins is
increased, suggesting both an increase in
glomerular permeability (to allow the filtration
of albumin) and a reduction in proximal
reabsorption.
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If the patient is younger than age 30 and has documented
proteinuria on more than one occasion. This test detects
orthostatic proteinuria, a relatively common finding in
adolescents (occurring in 2 to 5 percent), but an
uncommon disorder in those over the age of 30 .
 Orthostatic proteinuria is characterized by increased
protein excretion in the upright position, but normal
protein excretion when the patient is supine
?neurohumoral activation and altered glomerular
hemodynamics
 Total protein excretion is generally less than 1 g/day in
orthostatic proteinuria, but may exceed 3 g/day in
selected patients.
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Orthostatic proteinuria is a benign condition
requiring no further evaluation or specific
therapy .In many patients, the condition
resolves over time.
 Many patients with glomerular disease will have
a modest reduction in protein excretion when
supine. However, the diagnosis of orthostatic
proteinuria requires that protein excretion be
normal when supine (less than 50 mg per 8
hours), not merely less than when in the upright
position
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Split urines are collected according to the following
protocol .
o A 16-hour upright collection is obtained between 7 AM
and 11 PM, with the patient performing normal
activities and finishing the collection by voiding just
before 11 PM. (The times can be adjusted according to
the normal times at which the patient awakens and
goes to sleep.)
o The patient should assume the recumbent position 2
hours before the daytime collection is finished to
avoid contamination of the supine collection with
urine formed when in the upright position.
o A separate overnight 8 hour collection is obtained
between 11 PM and 7 AM.
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Instead of the cumbersome 24-hour urine
collection, the protein-to-creatinine (Pr/Cr)
ratio may be used on a first morning spot
urine specimen and on a specimen collected
while upright. For this, the patient is
instructed to void before going to bed and to
remain recumbent until the first morning
sample is obtained.
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A thorough evaluation
Underlying renal or systemic disorder .
Renal function tests :BUN and Cr
,quantitative measurement of urine protein,
ultrasound examination
All patients with persistent proteinuria
should be referred to a nephrologist for
decisions regarding further management
(eg, renal biopsy).
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A renal biopsy is performed if there is some sign
of severe or progressive disease, such as
nephrotic syndrome, increasing protein
excretion, or an elevation in the plasma
creatinine concentration.
Biopsies are often not performed among
patients with stable non-nephrotic proteinuria,
providing renal function is stable and hematuria
is not present, since knowledge of histology
obtained by the biopsy is unlikely to alter
therapy.
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The level of non-nephrotic proteinuria that
should be evaluated by biopsy is not clear.
Perform a biopsy in patients with non-nephrotic
proteinuria of 2 to 3 g/day but not for proteinuira
that is less than 1 g/day .If a patient with
proteinuria greater than 1 g/day is reluctant to
undergo biopsy, absolute indications include
increasing proteinuria or plasma creatinine
concentration, or a significant elevation in blood
pressure over baseline values.
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The prognosis of patients with glomerular
proteinuria is related to the quantity of protein
excreted. Non-nephrotic proteinuria (less than 3
g/day) is associated with a much lower risk of
progressive chronic kidney disease than
nephrotic range proteinuria.
These observations indicate the need for
persistent monitoring of patients with
apparently benign, nonorthostatic, and
persistent isolated proteinuria.
 Is not a disease
but a group of signs and
symptoms seen in patients with heavy
proteinuria
 Presents with edema
 proteinuria usually > 3.5g / 24hrs (>0.05g / kg /
24hrs in children)
 serum albumin < 30g/L
 other features:
hyperlipidaemia, and hypercoaguable state
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Proteinuria > 3.5 grams/day
Hypoalbuminemia
Edema
Lipiduria
Hyperlipidemia
 Proteinuria: due to an increase in glomerular
permeability
 Hypoalbuminemia: occurs when liver synthesis cannot
keep up with urine losses
Edema mechanism is complex and still in dispute: primary salt
and water retention associated with reduced renal function as
well as reduced plasma oncotic pressure are primary factors
(overfill and underfill)
Minimal change disease fits the underfill theory best
 Hyperlipidemia: increased liver synthesis
 Hypercoagulation: increased fibrinogen and loss of
antithrombin III
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Primary
Membranous Glomerulopathy
Focal Segmental Glomerulosclerosis
Minimal Change Disease
Membranoproliferative GN
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Secondary
Diabetic glomerulosclerosis
Paraproteinemia /Amyloidosis
Lupus Nephritis
 Systemic diseases
 diabetes mellitus
 amyloidosis
 SLE and other connective tissue diseases
 HIV/Aids
 nephrotoxins
 nsaids
 mercury poisoning
 penicillamine
 gold salts
Allergies
bee sting
pollens
poison ivy
Circulatory effects
congestive cardiac failure
constrictive pericarditis
renal vein thrombosis (cause or result?)
Neoplastic
leukemia
solid tumors
Nephrotic syndrome
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Nephrotic range proteinuria
– adults
>3.0-3.5 grams/d
– children >40 mg/h
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Defining Clinical features
– Proteinuria
causes Hypoalbuminemia
– Edema - altered Starling forces
– Hyperlipidemia - increased liver production of
beta lipoprotein, decreased lipoprotein lipase,
decreased conversion of Free fatty acid to
triglycerides
Nephrotic syndrome
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Hypercoagulable
– urinary
loss of anti-thrombin III and plasminogen
– hemoconcentration
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Risk of Infections
-urinary loss of gamma globulin
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History and Physical Exam
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Urine Analysis
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Lab Studies
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Renal Biopsy
Urine Sediment Types
Nephritic urine
red cells (hematuria)
Nephrotic urine
heavy proteinuria
Chronic GN
proteinuria
variable proteinuria
free fat droplets
granular casts
fatty casts
variable
hematuria
broad waxy casts
24 urine collection
Serum electrolytes, BUN, creatinine, lipid profile,
serum albumin
 Serological work up - depends upon the clinical
presentation - common serological tests done are:
ANA; Anti-ds DNA Complement levels (C3, C4)
Hepatitis B and C serologies SPEP; UPEP, ANCA,
anti GBM Abs
 Renal Ultrasound
 Renal Biopsy
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Na+< 60 mmol/24 hrs
water restriction
diuretics (if not volume depleted)
reduced protein diet (controversial)
treat infections
 prophylaxis for thrombosis
 specific therapy
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 corticosteroids
 immunosuppression
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Edema - salt restriction, diuretics
Hyperlipidemia - lipid lowering agents
ACE/ARB  decrease Pgc and decrease proteinuria
 Renal protective
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Hypercoagulable - ASA
Specific treatment based on biopsy
Minimal change disease
prednisone for 16 weeks (p)
prednisone and cyclophosphamide ( p+c)
FSGS
p, p+c, p+cyclosporine(cs)
Membranous
Ponticelli Regimen
p+c
Most common in children
Etiology:
Idiopathic
Drugs – NSAID
Toxins – Mercury, Lead
Infections – HIV, Mononucleosis
Tumors – Hodgkin disease
 Patient usually normotensive, nephrotic sediment,
normal renal function.
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Pathogenesis - unknown, most likely
autoimmune
Treatment
 85% respond to steroids
 If resistant to steroid may require
cyclophosphamide
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Most common primary renal disease in
African-Americans
Etiology:
Idiopathic
Drugs – Intravenous heroin
Infections – HIV
Others – reflux nephropathy, obesity
Patient usually hypertensive. Usually
progresses to ESRD over 5-20 years.
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Pathogenesis
 Primary - immunologic?
 Secondary - common end point of many
renal diseases
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Treatment
 Steroids
 Immunomodulators - cyclosporine,
Tacrolimus, mycophenolic acid
 ACE/ARB and anti-lipid agents
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Most common cause of idiopathic nephrotic
syndrome in Caucasian adults.
Heavy proteinuria is common. Hypertension
and azotemia develops as disease progresses.
Increased incidence of renal vein thrombosis.
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Primary
 Autoantibody to glomerular antigen
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Secondary
 Circulating antigen deposits
 Antibody to antigen attaches causing
immune reaction
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In both
 Complement activated and cell damage due
to C5-9 attack complex
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Rule of 1/3
1/3 – Spontaneous remission
1/3 – Partial remission / slow deterioration
1/3 – Progress to ESRD
 Steroids alone are not very effective
 Methylprednisolone alternating with chlorambucil,
Methylprednisolone alternating with
cyclophosphamide.
 Cyclosporin
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1-Declining renal function
2- Persistent proteinuria
3-Amount of proteinuria at the time of presentation
4-male sex
5-Advanced age (>50)
6-Poorly controlled HTN
7-Crescents on renal biopsy
8-The presence of frequent mononuclear cells in the
interstitium
9-FSGS superimposed on membranous glomerulopathy
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Most common cause of nephrotic syndrome in
adults.
Leading cause of ESRD in USA
30% of patients with Type I and 20% of patients
with Type II DM develop diabetic nephropathy.
Initially microalbuminuria followed by heavy
proteinuria and decline in renal function.
Diagnosis usually made on clinical grounds and
biopsy not needed.
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Glomerular Hyperfiltration
 Efferent arteriolar vasoconstriction
 Afferent arteriolar vasodilation
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Hyperglycemia
 Advanced glycation endproducts
 Glycation of proteins
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Blood glucose control
Control of hypertension
Use of ACE inhibitors/ARBs
Control of hyperlipidemia
Smoking cessation
Protein Restriction
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Myeloma Cast Nephropathy
 Disease of older adults
 Usually presents with
▪ Bone pain
▪ Hypercalcemia
▪ Pathologic fractures
▪ anemia
▪ Proteinuria - consists of monoclonal immunoglobulins
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Myeloma Cast Nephropathy
 Path. shows multiple intraluminal
proteinaceous casts
 Pathogenesis
▪ Disorder of plasma cells with overproduction of
the antibody light chain
 Treatment
▪ Hydration, plasmapheresis to remove the
abnormal protein and chemotherapy to suppress
plasma cells
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Primary Amyloid
 Amyloid deposition in heart, GI Tract, Skin, nerves and
tongue
 No bone lesions or excess marrow plasma cells
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Secondary amyloid
 Chronic Inflammatory conditions
 Tuberculosis, Chronic osteomyelitis, Rheumatoid arthritis,
ulcerative colitis, Hodgkins Disease
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Amyloid protein produced in plasma cell
dyscrasias is preferentially lamda light chains
Kappa chain can occur and termed light chain
deposition disease
Kappa chain deposits tend to deposit in
tubules and glomeruli, spare vessels
Kappa more aggressive than lambda
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Hematuria that is not explained by an
obvious underlying condition is fairly
common. In many such patients, particularly
young adult patients, the hematuria is
transient and of no consequence .On the
other hand, there is an appreciable risk of
malignancy in older patients (eg, over age 40)
with hematuria, even if transient .However,
even among older patients, a urologic cause
for the hematuria can often not be identified .
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Gross hematuria is suspected because of the
presence of red or brown urine. The color
change does not necessarily reflect the
degree of blood loss, since as little as 1 mL of
blood per liter of urine can induce a visible
color change.
Gross hematuria with passage of clots almost
always indicates a lower urinary tract source.

As contamination with blood is a possibility in
menstruating and post-partum women, urine
for analysis is best obtained when the other
cause of bleeding has ceased. If this is not
possible a tampon can be inserted, and
urinalysis obtained after the perineum is
thoroughly cleansed.
The initial step in the evaluation of patients with
red urine is centrifugation of the specimen to see
if the red or brown color is in the urine sediment
or the supernatant.
 Hematuria is responsible if the red to brown
color is seen only in the urine sediment, with the
supernatant being clear.
 If it is the supernatant that is red to brown, then
the supernatant should be tested for heme
(hemoglobin or myoglobin) with a urine dipstick.
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A red to brown supernatant that is negative
for heme (hemoglobin or myoglobin) is a rare
finding that can be seen in several conditions,
including porphyria ,the use of the bladder
analgesic phenazopyridine, and the ingestion
of beets in susceptible subjects.
Medications: Doxorubicin, Chloroquine
Deferoxamine, Ibuprofen ,Iron, sorbitol,
Nitrofurantoin ,Phenazopyridine,
Phenolphthalein, Rifampin.
 Food dyes :Beets (in selected patients),
Blackberries, Food coloring.
 Metabolities: Bile pigments, Homogentisic
acid, Melanin, Methemoglobin, Porphyrin ,
Tyrosinosis, Urates.
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Microscopic hematuria may be discovered by
accident when blood (either red blood cells or
hemoglobin) is found on a urinalysis or
dipstick done for other purposes.
Although abnormal hematuria is commonly defined
as the presence of more than 2 RBCs per high power
field in a spun urine sediment, there is no "safe" lower
limit below which significant disease can be excluded .
 Some experienced clinicians prefer to define
hematuria by quantitative counting of RBCs in a
hemocytometer chamber. A count of more than 8000
per mL in centrifuged urine (with back calculation to
the original volume of the urine sample) or 13,000 per
mL in uncentrifuged urine is considered abnormal .
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The urine sediment (or direct counting of RBC per mL of
uncentrifuged urine) is the gold standard for the detection
of microscopic hematuria. Dipsticks for heme detect 1 to 2
RBCs per high power field and are therefore at least as
sensitive as urine sediment examination, but result in
more false positive tests due to the following:
Semen is present in the urine after ejaculation and may
cause a positive heme reaction on the dipstick .
An alkaline urine with a pH greater than 9 or
contamination with oxidizing agents used to clean the
perineum.
The presence of myoglobinuria.
positive dipstick test must always be confirmed with
microscopic examination of the urine
The identification of the glomeruli as the source of
bleeding is important both prognostically and to
optimize the subsequent evaluation. In particular,
patients with clear evidence of glomerular hematuria
do not need to be evaluated for potentially serious
urologic disease .
 Glomerular hematuria may result from immunemediated injury to the glomerular capillary wall, or in
noninflammatory glomerulopathies such as thin
basement membrane nephropathy from localized
gaps in the glomerular capillary wall.
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signs of glomerular bleeding (best identified by a
nephrologist or other experienced examiner)
include red cell casts (considered by most to be
pathognomonic for glomerular disease,
although rarely described in acute interstitial
nephritis), protein excretion exceeding 500
mg/day at a time when there is no gross
bleeding, a dysmorphic appearance of some red
cells (particularly acanthocytes, which are best
seen by phase contrast microscopy), and brown,
cola-colored urine with gross hematuria.

An additional important abnormality that
may be seen in patients with hematuria is
blood clots. Clots virtually never occur in
glomerular disease, perhaps due to the
presence of urokinase and tissue-type
plasminogen activators in the glomeruli and
the renal tubules.
As a general principle, hematuria itself is not
dangerous unless extraglomerular bleeding is so
brisk that it causes clots that obstruct the
ureter(s).
 The evaluation should address the following
three questions:
 Are there any clues from the history or physical
examination that suggest a particular diagnosis?
 Does the hematuria represent glomerular or
extraglomerular bleeding?
 Is the hematuria transient or persistent?

Concurrent pyuria and dysuria, which are usually
indicative of a urinary tract infection, but may also
occur with bladder malignancy.
 A recent upper respiratory infection raises the
possibility of postinfectious glomerulonephritis or IgA
nephropathy.
 A positive family history of renal disease, as in
hereditary nephritis, polycystic kidney disease, or
sickle cell disease.
 Unilateral flank pain, which may radiate to the groin,
suggests ureteral obstruction due to a calculus or
blood clot, but can occasionally be seen with
malignancy.
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
Symptoms of prostatic obstruction in older men
such as hesitancy and dribbling. there is general
agreement that the presence of BPH should not
dissuade the clinician from pursuing further
evaluation of hematuria, particularly since older
men are more likely to have more serious
disorders such as cancer of the prostate or
bladder. Among those with gross hematuria in
whom no other cause can be identified,
finasteride usually suppresses the hematuria.
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Recent vigorous exercise or trauma.
History of a bleeding disorder or bleeding from
multiple sites due to excessive anticoagulant
therapy.
Cyclic hematuria in women that is most prominent
during and shortly after menstruation, suggesting
endometriosis of the urinary tract .
Contamination with menstrual blood is always a
possibility, and should be ruled out by repeating
the urinalysis when menstruation has ceased.
Medications that might cause nephritis (usually
with other findings, typically with renal
insufficiency).
 Black patients should be screened for sickle cell
trait or disease, which can lead to papillary
necrosis and hematuria.
 Travel or residence in areas endemic for
Schistosoma haematobium or tuberculosis.
 Sterile pyuria with hematuria, which may occur
with renal tuberculosis, analgesic nephropathy
and other interstitial diseases.

The main indication for performing a renal biopsy in
patients with isolated glomerular hematuria is
evidence of progressive disease as manifested by
increasing protein excretion and/or an elevation in the
serum creatinine concentration
 Renal biopsy is not usually performed for isolated
glomerular hematuria (ie, no proteinuria and no
elevation in serum creatinine), since there is no
specific therapy for these conditions and the renal
prognosis is excellent as long as there is no proteinuria
or elevation in serum creatinine.
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There is no cause of low-level hematuria that, in the absence of
other signs and symptoms, requires immediate diagnosis. As a
result, it is reasonable to repeat an abnormal urinalysis in a few
days to determine if hematuria is transient or persistent.
Transient microscopic hematuria is a common problem in adults.
No obvious etiology can be identified in most patients with
transient hematuria.
Fever, infection, trauma, and exercise are potential causes of
transient hematuria. Transient hematuria can also occur with
urinary tract infection
An important exception to the typically benign nature of transient
hematuria occurs in patients over age 40 in whom even transient
hematuria carries an increased risk of malignancy

All patients should have a urine culture to
exclude infection prior to evaluation of
hematuria. The urinalysis should be
rechecked in six weeks to determine whether
hematuria has resolved. Patients who have
resolution of hematuria do not require further
evaluation.
A voided urine specimen should be sent for cytology in
patients at increased risk for urothelial cancers.
 The sensitivity of urine cytology is greatest for carcinoma
of the bladder (approximately 90 percent). By comparison,
sensitivity for upper tract transitional cell carcinoma is
limited.Urine cytology is frequently obtained during
cystoscopy, which is usually performed in patients at risk
for malignancy.
 Among patients at low risk for genitourinary cancer, some
investigators recommend that either urine cytology or
cystoscopy be performed .Cystoscopy is subsequently
done if malignant and/or atypical/suspicious cells are
identified.
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Once glomerular bleeding has been excluded
in a patient with otherwise unexplained
hematuria, the diagnostic work-up should
include a search for lesions in the kidney,
collecting system, ureters, and bladder.
The diagnostic yield in adults increases with
age and may be higher for gross hematuria
than for microscopic hematuria.
The optimal radiologic evaluation for isolated
hematuria is uncertain


A number of modalities are available to evaluate
the genitourinary tract among patients with
unexplained hematuria. These include
conventional radiography, IVP, retrograde
pyelography, ultrasonography,MRI,MRU,
conventional CT scanning, and multidetector CT
urography.
Patients with malignancy in the bladder or
kidneys are at increased risk for malignancy at
the other site and should undergo further
evaluation.

Screening for hematuria in patients who
have no symptoms suggestive of urinary tract
disease is not recommended.

Polyuria has generally been defined as a
urine output exceeding 3 L/day in adults. It
must be differentiated from the more
common complaints of frequency or nocturia,
which are not associated with an increase in
the total urine output.

In the absence of a glucose-induced osmotic
diuresis in uncontrolled diabetes mellitus,
there are three major causes of polyuria in
the outpatient setting, each of which is due
to a defect in water balance leading to the
excretion of large volumes of dilute urine
(urine osmolality usually below 250
mosmol/kg): primary polydipsia, which is
primarily seen in adults and adolescents;
central DI; and nephrogenic DI .

Primary polydipsia also called psychogenic
polydipsia :a primary increase in water intake.
This disorder is most often seen in anxious,
middle-aged women and in patients with
psychiatric illnesses, including those taking a
phenothiazine which can lead to the sensation
of a dry mouth. Primary polydipsia can also be
induced by hypothalamic lesions that directly
affect the thirst center, as may occur with an
infiltrative disease such as sarcoidosis.
 Central DI also called neurohypophyseal or
neurogenic DI is associated with deficient
secretion of ADH. This condition is most often
idiopathic (possibly due to autoimmune
injury to the ADH-producing cells), or can be
induced by trauma, pituitary surgery, or
hypoxic or ischemic encephalopathy. Rare
familial cases have been described.

Nephrogenic DI is characterized by normal
ADH secretion but varying degrees of renal
resistance to its water-retaining effect. This
problem, in its mild form, is relatively common,
since most patients who are elderly or who have
underlying renal disease have a reduction in
maximum concentrating ability. This defect,
however, is not severe enough to produce a
symptomatic increase in urine output.
Symptomatic polyuria due to ADH-resistance
is seen primarily in 2 settings :
 Nephrogenic DI presenting in childhood is
almost always due to inherited defects.
 Nephrogenic DI presenting in adults is almost
always acquired with chronic lithium use and
hypercalcemia being the most common
causes of a defect severe enough to produce
polyuria.


The cause of polyuria is often suggested from
the history (eg, age of onset and eliciting the
possible presence of the different causes of
DI), and rarely by the plasma sodium
concentration. Specific testing is then
performed to establish the diagnosis.
Onset of polyuria :
In the majority of cases of hereditary nephrogenic
DI, severe polyuria manifests during the first week of
life.
 In familial central DI (usually an autosomal dominant
disease), polyuria may present after the first year of
life, sometimes in young adulthood, due to
preservation of function of the normal allele.
 In adults, the onset is usually abrupt in central DI ("I
suddenly began urinating too much a few days ago"),
and almost always gradual in acquired nephrogenic
DI or primary polydipsia.

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
The new onset of nocturia in the absence of
other causes of nocturia is often a first clue to
DI. The urine is normally most concentrated
in the morning due to lack of fluid ingestion
overnight; as a result, the first manifestation
of a loss of concentrating ability is often
nocturia.


Family history : There are familial forms of
both central and nephrogenic DI.
A family history of polyuria is helpful both for
diagnosis and to identify asymptomatic
members of affected families who harbor the
suspect allele. Thus, all families with
hereditary DI should have their molecular
defect identified.

Plasma sodium and urine osmolality: Each of
the three causes of polyuria is associated with
an increase in water output and the excretion
of a relatively dilute urine. With primary
polydipsia, the polyuria is an appropriate
response to enhanced water intake; in
comparison, the water loss is inappropriate
with either form of DI.
Measurement of the plasma sodium concentration and
the urine osmolality may be helpful in distinguishing
between these disorders:
 A low plasma sodium concentration (less than 137 meq/L)
with a low urine osmolality (eg, less than one-half the
plasma osmolality) is usually indicative of water overload
due to primary polydipsia.
 A high-normal plasma sodium concentration (greater than
142 meq/L, due to water loss) points toward DI,
particularly if the urine osmolality is less than the plasma
osmolality .
 A normal plasma sodium concentration is not helpful in
diagnosis but, if associated with a urine osmolality more
than 600 mosmol/kg, excludes a diagnosis of DI.


Measurement of urine output : Potential
problems include an incomplete collection
and the necessity for multiple containers if
the patient has severe polyuria, which can be
minimized by obtaining an eight hour rather
than a 24 hour collection. Measurement of
urinary creatinine excretion can help
determine if the collection is complete.

Water restriction test : Even if the history
and/or plasma sodium concentration and
urine osmolality appear to be helpful, the
diagnosis should be confirmed by raising the
plasma osmolality either by water restriction
.Water restriction is important to
differentiate central DI from primary
polydipsia; simply giving exogenous ADH.

Plasma and urine ADH measurement —
Unless the history and water restriction test
provide unequivocal results

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SOLUTE DIURESIS:
Glucosuria is the major cause of an osmotic diuresis in
outpatients, but other conditions are often responsible when
polyuria develops in the hospital. These include high-protein
feedings (in which urea acts as the osmotic agent) and
volume expansion due to saline loading or the release of
bilateral urinary tract obstruction.
A solute diuresis can be differentiated from diabetes
insipidus based upon the following findings:
The urine osmolality
Total solute excretion