1. health and fitness
2. disease

Diagnostics and main causes of
proteinuria in children
Prof. dr hab. Anna Wasilewska
Hippocrates Aphorisms
460--377 B.C
460
“Bubbies appearing on the surface of
the urine indicate renal disease and a
prolonged illness”
1
Richard Bright - (1789-1858)
Proteinuria
Glomerular
Tubular
Overload
Benign
2
Mechanism of proteinuria
Size of protein
Shape of protein
Charge of protein
Renal hemodynamics
Proteinuria and Nephrotic syndrome
Definitions
Physiology
Physiological proteinuria
Classification of proteinuria
Urine dipstick
Investigation of proteinuria
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Definitions
Proteinuria
Urine protein excretion > 150mg/day
Microalbuminuria
Urine [albumin] > 30mg/day but not
detectable by urine dipstick
Nephrotic syndrome
Urine protein excretion > 3.5g/day (with
hypoalbuminaemia,, oedema and
hypoalbuminaemia
hyperlipidaemia))
hyperlipidaemia
Normal physiology
Protein filtration through the glomerulus is
dependent on the protein size, shape and
electrical charge
4
Normal physiology
Protein charge
At physiological pH, most proteins are
negatively charged
Since the basement membranes are also
negatively charged, most proteins are
retained
Normal physiology
Protein size
Proteins greater than 40kDa are almost
completely retained
Thus, only small proteins, e.g. retinolretinol-binding
protein, ß2 microglobulin, passes into the
ultrafiltrate
5
Normal physiology
However, most of the filtered proteins are
reabsorbed by the proximal tubules.
Consequently, very little plasma protein
appears in the urine
Normally < 150mg/24hours
“Physiological” proteinuria
In some nonnon-pathological situations, a
higher than normal urine protein level is
found:
A concentrated spot urine
Exercise
Orthostatic proteinuria
Contamination e.g. from vagina
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Classification
Tubular proteinuria
Tubular dysfunction
Overflow proteinuria
Glomerular proteinuria
Selective proteinuria
Non--selective proteinuria
Non
microalbuminuria
Tubular proteinuria
This occurs when glomerular function is
intact, but protein is lost to the urine
either because of:
Tubular dysfunction
Overflow
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Tubular proteinuria
Tubular dysfunction
The tubules are damaged and cannot function
properly
Therefore, the small MW proteins that are
normally filtered are not reabsorbed by the
tubules
The small MW proteins include: retinolretinolbinding protein, ß2 microglobulin, lysozyme,
light chains, haemoglobin, myoglobin
Tubular proteinuria
Tubular dysfunction
Pyelonephritis
Acute tubular necrosis
Papillary necrosis e.g. analgesic nephropathy
Heavy metal poisoning
SLE
Fanconi’s syndrome
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Tubular proteinuria
Overflow proteinuria
Occurs when the concentration of one of the
small MW proteins is so high that the filtered
load exceeds the tubular reabsorptive
capacity
Thus, the excess filtered load appears in the
urine
Tubular proteinuria
Overflow proteinuria
Bence Jones proteinuria
Myoglobinuria
Haemoglobinuria
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Glomerular proteinuria
When there is glomerular dysfunction,
proteins > 40kDa can escape into the
urine
The most common form of proteinuria
Glomerular proteinuria
Selective proteinuria
Non--selective proteinuria
Non
Microalbuminuria
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Glomerular proteinuria
Selective proteinuria
If only intermediateintermediate-sized (< 100kDa)
proteins (albumin, transferrin), leaks through
the glomerulus, this is termed selective
proteinuria
Glomerular proteinuria
Non--selective proteinuria
Non
When a range of different sized proteins leak
through including larger proteins (IgG), this is
termed nonnon-selective proteinuria
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Glomerular proteinuria
Selectivity
The measurement of the selectivity of
proteinuria used to be popular, however,
this has been replaced by renal biopsy and
electron microscopy
Glomerular proteinuria
Causes
Glomerulonephritis
Diabetes mellitus
Multiple myeloma
Amyloidosis
SLE
PrePre-eclampsia
Penicillamine, gold
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Glomerular proteinuria
Microalbuminuria
Urine albumin concentrations which are
greater than normal but not detectable by
urine dipstick
Microalbuminuria
Normal urine protein: 150mg/day
About 1515-20 mg of the normal urine
protein is albumin
Urine dipsticks detects urine albumin
>300mg/day
13
Microalbuminuria
Therefore, microalbuminuria is defined as:
Urine albumin excretion 30
30--300mg/day
Or
Urine albumin excretion rate 20
20-200ug/min.
Microalbuminuria
Microalbuminuria is not detectable by
dipsticks
Therefore, a 24hr or 12 hr urine collection
is required
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Microalbuminuria
Clinical significance:
Correlates with mortality in diabetics and
hypertensives
Predicts the development of nephropathy in
Type 1 and Type 2 diabetes
Microalbuminuria
Treatment:
Good BP control, especially by ACEACE-inhibitors
And
Good diabetic control
Postpones the development of diabetic
nephropathy
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Detection of proteinuria
Shaking
Boiling
Salicylosulphonic acid
Reagent strip
Detection of protein
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Detection of proteinuria
Reagent strips:
strips:
Trace – approx 150 mg/l
1+ - approx 300 mg/l
Urine dipstick
Commonly used for screening of
proteinuria
Is a plastic strip impregnated with a pH
indicator which changes colour in the
presence of proteins, due to a pH change
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Urine dipstick
The intensity of the colour correlates with
the concentration of protein in the urine
Mainly detects albumin, and therefore
glomerular proteinuria
Sensitivity: 0.1g/l
Urine dipstick
False positives:
When urine is alkaline (some UTI)
The urine is pigmented (haematuria)
The urine is concentrated
Drug / chemical interference (chlorhexidine)
Contamination with vaginal secretions
Addition of egg white
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Urine dipstick
False negatives:
The protein is not albumin
The urine is dilute
Clinical history
Incidental finding
Evidence of renal disease
Evidence of systemic illness
Family history of renal disease
Medications being taken
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Initial investigation
Renal function
Urine dipstick
Determine the amount of protein detected
Initial investigation
If renal function is normal
and
If protein is trace or 1+
and
There is no significant clinical history
then
Repeat testing
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Initial investigation
When urine dipstick is repeated, ask the
patient to:
Refrain from exercise for few hours
Collect early morning urine to exclude
orthostatic proteinuria
Initial investigation
If the findings are negative upon repeat
testing, then the initial positive result may
be due to a transient proteinuria (e.g.
fever, exercise)
Or
A false positive
21
Further investigation
Further investigation is needed if:
Still positive upon repeat testing
Positive clinical history
Abnormal renal function
Initial urine protein is > 1+
Prognosis
Underlying disease process
Amount of protein excreted
22
What should we do ?
Further investigation
24 hour urine protein excretion
Creatinine and creatinine clearance
Urine microscopy
Other relevant tests dependent on the
provisional diagnosis
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24 hour urine protein excretion
Gives a more accurate assessment of the
severity of the proteinuria
> 150mg/24 hour = proteinuria
> 3.5 g/24 hour (with associated features)
= nephrotic syndrome
For estimation of 24hr urine albumin if
suspect microalbuminuria
Creatinine and creatinine clearance
And estimation of GFR
Assesses severity of renal dysfunction
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Urine microscopy
To look for casts, white cells and red cells
May be a clue to the diagnosis of
glomerulonephritis, pyelonephritis, tubular
damage
Other tests
Renal ultrasound if suspect renal disease
Renal biopsy if suspect glomerular disease
Plasma and urine electrophoresis if
suspect multiple myeloma with Bence
Jones proteinuria
Urine for myoglobin / haemoglobin
HbA1c to assess diabetic control
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The most frequent diseases
leading to nephrotic
syndrome in children.
Prof. dr hab. Anna
Wasilewska
Nephrotic syndrome
The term nephrotic syndrome is
applicable to any condition with heavy
proteinuria, hypoproteinemia, and
edema.
It is a disorder of glomerular
permselectivity that may be primary or
secondary to an overt systemic disease.
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Nephrotic syndrome
In children the most common variety is
MCNS with a characteristic response to
corticosteroid therapy
But a few patients with MCNS do not
respond to steroids , and a few steroid
responders have histology other than
MCNS.
Nephrotic syndrome: Definitions
Nephrotic syndrome:
syndrome: edema, plasma
albumin less 2.5 gm/dl, proteinuria >40
mg/m2/h
Remission: urinary protein excretion < 4
mg/m2/h or dipstick neg/trace for 3
consecutive days
Steroid response: remission achieved with
steroid therapy alone
Late responder: remission occurring after 4
weeks prednisolone 60 mg/m2/day
without other drugs
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Definitions
Relapse: urinary protein excresion >40
mg/m2/h or dispstick 2+ for 3 consecutive
days having previously been in remission
Frequent relapses: two or more relapses
within 6 months of initial response or 4 or
more in 12 months
Steroid dependence: two consecutived
relapses occurring during corticosteroid
treatment or within 14 days of cessation
Definitions
Steroid resistance: failure to achieve response
in spite 8 weeks of prednisolone 60 mg/m2/day
Early nonresponder: steroid resistance in the
initial episode
Late nonresponder: steroid resistance
developing in a patient who had previously been
steroid responsive
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Idiopathic nephrotic syndrome
Children with steroidsteroid-resistant NS may
have one of several different histologic
appearances in the glomeruli,
glomeruli, being
most common FSGS.
It is not clear if MCNS and FSGS should
be consider two different entities or
different ends of a single spectrum of
disease.
Idiopathic nephrotic syndrome
Current opinion is to include both conditions under
the single label of Idiopathic Nephrotic
Syndrome, dividing into steroidsteroid-sensitive (SSNS)
and steroidsteroid-resistant (SRNS).
Patients with SRNS have higher risk for extrarenal
complications as well as pro
progression to CRF and
ESRD, with high recurrence in the graft after
transplantation.
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INS: Epidemiology
Prevalence is ~16/100000 children, annual
incidence of 22-7/100000 children
Ratio M/F is 2/1, in younger children. This
male predilection disappears in teenagers
and adults
3/4 less than 6 years
INS: Epidemiology
Median ages at time of presentation varies
according to histopathological diagnosis: 3
years for MCNS, 6 years for FSGS and 10
years for MPGN
Majority of patients that have SSNS has
MCNS. The risk of progressing to CRF and
ESRD for SRNS is 40% in 5 years.
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Epidemiology
Familial incidence
European survey 63 of 1877 nephrotic
children had affected siblings
Familial NS bred true with respect to
histopathology and steroid response
Associated Disorders
Atopy has been found in 3434-60% of
children with MCD
Meadow reported plasma IgE levels elevated
in 10 of 84 with MCD
Malignancy
Hodgkin’s disease
T cell lymphomas
Thymoma/ myasthenia gravis
Diabetes Mellitus
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Clinical FeaturesFeatures- Edema
Physical exam
Accumulates in
gravity dependent
tissues
Puffiness around
eyes
Genital edema is
generally painful
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Clinical FeaturesFeatures- Edema
Pathogenesis
80% of oncotic pressure due to albumin
Below 2 g/dL edema accumulates
Intravascular volume depletion
Renin--aldosterone activation
Renin
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Clinical FeaturesFeatures- Hypovolemia
Classic teaching
Not all patients are hypovolemic
Clinical FeaturesFeatures- Infection
Bacterial infections
Prone to bacterial sepsis
Cellulitis
IgG levels low
Factor B levels low
Lymphocyte function impaired
Viral Infections
Measles may induce remission in NS
Relapse preceded by viral infection
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Clinical FeaturesFeatures- Thrombosis
Serious risk of thrombosis
Increased fibrinogen concentration
Antithrombin III concentration reduced
Platelets hyperaggregable
Increased blood viscosity
Laboratory Features
Hct may be elevated
Hyponatremia is common
Plasma creatinine is elevated in 33% of
patients
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Laboratory-- Plasma Protein
Laboratory
Albumin
Hypoalbuminemia due to loss via the kidney
Urinary excretion
Proximal tubular cells catabolism
Immunoglobulins
IgG levels reduced
IgM levels elevated
Laboratory-- Hyperlipidemia
Laboratory
Increased synthesis of cholesterol,
triglycerides and lipoproteins
Decreased catabolism of lipoproteins
Decreased activity of lipoprotein lipase
Decreased LDL receptor activity
Increased urinary loss of HDL
Lp(a) levels are elevated
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Laboratory-- Urinalysis
Laboratory
Broad, waxy casts
Lipid droplets
Low urine sodium
High osomolality
Laboratory-- Proteinuria
Laboratory
> 40 mg/hour * m2
Urine protein/creatinine ratio > 2
Unusual to see tubular proteinuria
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Indications for Biopsy
Pretreatment
Recommended
Onset age < 6 months
Macroscopic hematuria
Microscopic hematuria and HTN
Low C3
Renal failure
Discretionary
Onset between 66-12 months or > 12 years
Persistent HTN of hematuria
Indications for Biopsy
Post treatment
Steroid resistance
Frequent relapsers
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Nephrotic Syndrome - treatment
Goals
Reduce urinary protein excretion
Reduce tissue fluid retention
Prevent infection
Minimize complication
Therapeutic Management
Low salt diet
Corticosteroids
Albumin and lasix
Immunosuppressants
Treatment-- Diet
Treatment
Low protein
Decreases albuminuria
Malnutrition
Salt restriction
During edema
Calorie control
Steroids
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Treatment- Antibiotics/
TreatmentImmunizations
Gram negative coverage for peritonitis
Streptococcal immunization
Varicella
VZIG if exposed
Immunizations
No live viruses while on daily steroids
Treatment-- Albumin
Treatment
Controversial
Indication-- Hypovolemia
Indication
Abdominal pain
Hypotension
Oliguria
Renal insufficiency
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Corticosteroids Initiation
High dose steroids
2 mg/kg/day (max 80 mg)
60 mg/m2 (max 80 mg)
3 accepted protocols
80% respond within 2 weeks
Corticosteroids Initiation
The intensity and duration of the initial
corticosteroid regime influences the rate
of relapse of NS
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Corticosteroids-- Relapse
Corticosteroids
60 mg/m2/day until remission
Change to alternate day
Taper over 11-3 months
Corticosteroids-- Maintenance
Corticosteroids
Individualized for each patient
Usually tapered over 6 monthsmonths- 1 year
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Steroid Toxicity
Cushingoid habitus
Obesity
Striae
Hirsutism
Acne
Growth failure
Avascular necrosis
Osteoporosis
Steroid Toxicity
Peptic ulceration
Pancreatitis
Posterior lens opacities
Myopathy
Increased ICP
Susceptibility to infection
43
Moon Face
High-dose
corticosteroid therapy
produces a characteristic
“moon face” appearance.
Before and After
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Indications for Alternative
Therapy--SSNS
Therapy
Relapse on Prednisone Dosage >0.5
mg/kg/alt day plus:
Severe steroid side effects
High risk of toxicitytoxicity- diabetes
Unusually severe relapses
Relapses on Prednisone Dosage >1.0
mg/kg/alt day
Options for Alternative TherapyTherapySSNS
Alkylating Agents
Cyclophosphamide
Chlorambucil
Levamisole
Cyclosporine
MMF
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Cyclophosphamide-- SSNS
Cyclophosphamide
8 weeks of 3 mg/kg/day
69% of children with SRNS remain in
remission for 1 year
44% for 5 years
Younger children do worse
Steroid dependent children do worse
2 mg/kg/day may or may not have any
benefit
Chlorambucil-- SSNS
Chlorambucil
0.2 mg/kg/day for 8 weeks
Sterility
10% incidence of azospermia with repeated
doses
Low incidence with chlorambucil < 8 mg/kg
total
Puberty
Leukopenia
Malignancy
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Levamisole-- SSNS
Levamisole
Antihelmithic with immunomodulating
properties
2.5 mg/kg/qOD for 2 months
British association for Pediatric Nephrology
Cyclosporine-- SSNS
Cyclosporine
5 mg/kg/day
Used with steroids
Patients usually respond well
Cyclosporine dependence is common
Long term side effects unknown
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