PAGE 1

Main points

Approach to children with proteinuria "Nephrotic Syndrome"

Dr. Rola alsqa'an

Approach
What controls
Glomerular
filtration?

Is it normal to have
tubular proteins?

What is TammHorsfall protein?

Describe the
structure of the
Glomerulus?

A. How the kidney Handle the proteins?

Three process Take place in the kidney:
1. Filtration What control the filtration of the proteins is two barriers: 1.charge barrier
(formed by the negative charge of the basement membrane) and the 2.size barrier
(formed by the Histological structure of the Glomerular capillaries) so Protein filtration
depends on its Size & the charge; so large proteins are not filtrated and the same thing
is applied for the Negatively charged proteins.
2. Reabsorbtion (Tubular reabsorbtion) it is normally a proximal Tubular reabsorbtion ,
clinically if we find tubular protein this could be due to Tubular defects like Renal
Tubular acidosis and Tubular destruction
3. Secretion Some proteins are secreted normally to the filtrate and these are known as
Tamm-Horsfall protein and in normal
individuals no other proteins should be
present in the urine.
B. What is the anatomy of the Glomerulus ?
Glomerulus is
a capillary tuft
surrounded
by Bowman's capsule in nephrons, it consist of:
1.Capillaries (Afferent arterioles branches)
that are covered from the inner side by
fenestrated endothelial cells, this give us 3D
shape just like the " "and by EM electron
microscope- it appears just like "" .
2. Podocytes, these cells covers the capillaries
from the outer side and it branches to give
interdigitating like extensions, between these
extensions there is a slit diaphragm which
controls protein passage, there are multiple
genes responsible for slit diaphragm structure
and integrity and any genetic defect within
these proteins can lead to a congenital type of Nephrotic protein known as (Infantile
Nephrotic syndrome).

Proteinuria
What is the
underlying
mechanisms of
proteinuria?

Proteinuria is the appearance of the proteins in the urine because of:

1. Increase Protein filtration: because of podocytes abnormalities.
2. Increase protein reabsorbtion: Tubular proteinuria due to tubulopathies like RTA-Renal
tubular acidosis-.
3. Increase protein Secretion : in the following cases
A. Patients with high protein production (E.g. Multiple Myeloma).
B. Increase renal load like in obese patients who have High GFR Glomerular filtration
rate- and also in Hypertensive patients and individuals with Single Kidney.

PAGE 2
Main points

How you can

measure protein
level in the urine?

What is the normal

value for protein
level in the urine?

In any patient with proteinuria there is 3 important questions you have to ask:
1. What is the amount of protein being excreted?
Tested by:
Semi-quantitative measures:
1.
a.
b.
c.
d.
2.

urine dipstick, it only checks for albumin as the following:

+3 300-1000 mg/dl (Suspect Nephrotic Syndrome)
+2 100-300 mg/dl
+1 30-100 mg/dl
0 <30 mg/dl

Sulfa salicylic acid test which detect all kinds of protein in the urine but it is less used
now days.

What is the most

accurate way to
measure urine
proteins?

Quantitative measures (More accurate):

1. 24 hours urine collection (most accurate),ask the patient to void in the toilette at 7 am
then order him to collect any urine come out during the next 24 hours and ask him at
the next 7 am to void in the bottle even if there is no desire to urinate then we
measure how much protein is there.
In pediatric ages:
- Normal < 4 mg / sq.meter/ hr.
- Abnormal 4-40 mg / sq.meter / hr.(abnormal but not nephrotic)
- Nephrotic > 40 mg / sq.meter / hr. (at this stage the liver can't compensate for
the ongoing loss of the protein, so the symptoms begin to appear at this stage).
2. Urine protein / creatinine ratio :
Normally the ratio is less than 0.2, if its more than 2.5 its abnormal, If its more than 3
its very significant and we call it (Nephrotic range proteinuria).
2. What type of protein being excreted?
Tested By ELIZA and it isn't done usually.

What do we mean
by orthostatic
proteinuria?

3. Under what condition protein being excreted? (I.e. When I will become terrified of
detecting protein in the urine?)
This depends on the causes:
Transient proteinuria fever, exercise, UTI and Hypovolemia (Gastroenteritis)"can
cause both proteinuria and hematuria".
Orthostatic proteinurianot nephrotic and self limited, it Takes place in adolescent
period and in athletes, it is usually incidental finding and whenever the test is
repeated this will give us the same result "proteinuria".
How to diagnose it?
1. Take two urine specimens, one after waking early in the morning before
moving, then after two hours walking around we take the second specimen, If
there is a difference(1st one is negative & the 2nd one is positive) this is postural
"orthostatic" Proteinuria.
2. 24hrs urine collection in 2 bottles one for the daytime and the other for night
then send it to the lab, in orthostatic proteinuria the finding will be:
*Night specimen <4mg/seq. meter/hr and *Daytime specimen>4mg/seq.m/hr

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Main points

What
investigations you
ask for in
persistent
proteinuria?

Persistent Proteinuria Persist for more than 6 months, whenever you find this
type of proteinuria you have to do further investigations: Check the blood pressure, Do
Urine analysis (to look for infections), KFT, electrolytes, ultrasound (always do it whatever
the condition because it is a simple test and not invasive), HIV, C3,C4 and Test for Hepatitis.
Note : HBV & HCV are associated with MGN (membranous glomerulonephritis)and
MPGN(membranoproliferative glomerulonephritis).

Note: For any patient with asymptomatic proteinuria and normal KFT then all what I have to
do is to follow the patient by 24 hours urine collection Test (once every 3 or 6 months) But
if the proteinuria is worsening then I have to check the Blood pressure and the Kidney
function of my patient if there is further worsening then I should do Renal biopsy.
Note: patients with proteinuria may have non-specific symptoms such as skin rash,
Joint swelling, myalgia, fatigue, diarrhea and many others.

Nephrotic Syndrome
Nephrotic Syndrome it isn't uncommon and you see it during this time of the year -winterdue to increase viral infections rate and viral infections is a known triggering factor for
Nephrotic syndrome.

What are the main

manifestations of
Nephrotic
syndrome?

It is a syndrome composed of 4 manifestations:

1. Nephrotic Range proteinuria: > 40 mg /M2/hr
2. Hypoalbuminemiabecause of protein loss that is accompanied by inability of the liver
to compensate for the ongoing loss.
3. Edema Because of albumin loss that decreases the vascular Oncotic pressure.
4. HyperLipidemia This is caused by two things: 1.while the liver is trying to
compensate for the ongoing protein loss it will also produce larger amount of lipoproteins.
2.There is a significant loss of the Lipase enzyme which is the one responsible for lipid
destruction.
Classification:
A. Primary Nephrotic syndrome
1. Bland Urine Sediment (i.e. the urine is clear, means no casts or RBCs in the urine, urine
sample is normal except for proteinuria).
Note: (if there is Active urine Sediments Casts and urine RBCs- this means that the patient
have both Mixed nephritic and nephritic syndromes).

What is the major

change in EM in
patient with
minimal change
disease?

2. It is Idiopathic (90% below 10 years), it is histologically classified into:

A. Minimal change (predominant type) Characterized by Effacement of the
podocytes on EM image with no histological changes in the light Microscope.
B. Focal Segmental Glomerulosclorosis (FSGS) In this type only part of the kidney
is affected "focal defect" and not all the Glomeruli are affected in that part just part of
them "Segmental defect", but because this type diffuse Progressively the eventual
outcome is total kidney defect.
C. Membranoproliferative Glomerulonephritis (MPGN) Here we have Mesangial
proliferation and the capillaries look enlarged and thick.

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Main points

Note: This class of nephrotic syndrome is also classified according to it is response to

steroids as the following: 1. 80% of them respond 2. 20% of them show no response.
Note: The main presentation of Minimal change nephropathy is Nephrotic Syndrome while the other
two types ((FSGS and MPGN)) can be presented as mixed nephritic and Nephrotic but primary
they are presented as Nephrotic syndrome.
B. Secondary Nephrotic syndrome

What is the
commonest type
of secondary
Nephrotic
syndrome?

1. PSGN (Post Streptococcal GlumeruloNephritis), endocarditis, shunt nephritis, syphilis,

leprosy, HIV, HBV, Drugs, Mercury, tumors (lymphomas and leukemias), SLE, HSP,
Vasculitis, Good-pasture's syndrome and hereditry causes are a well known disorders
associated with secondary Nephrotic syndrome.
Congenital Nephrotic syndrome

What it is the
etiology of Finnish
type congenital
Nephrosis?

1. May be due to genetic causes (defect in the genes that encodes the protein
components of the basement membrane) or due to other causes as Syphilis, Toxoplasma
and CMV.
2. It usually occurs in the first 3 months of life. ((If it occurred 3months-1year then it is
called Infantile Nephrotic syndrome)).
3. The most common type is Finnish type congenital Nephrosis (due to defect in the

gene that encodes for nephrin which is part of the slit diaphragm proteins).

Here is some additional points about the previously mentioned illnesses:

1. Minimal change disease

What are the

major clinical
findings in patient
with minimal
change disease?

Most common type of primary nephrotic syndrome in pediatrics population,

making up to 85% of the cases .

Happens usually between the age of 1-6 years.

Those patients have normal kidney function and no Hematuria,

Hypertension or abnormal complaints.

Clinical Findings: are those associated with protein loss:

1. The main protein that is lost is albumin which causes the presentation.
2. Loss of Vit-D binding protein leads to Ricketes.
3. Loss of Iron binding protein leads to Iron deficiency anemia.
4. Loss of Immunoglobulins leads to recurrent infections.
5. Loss of thyroid binding proteins ((occur mainly in congenital nephritic
syndrome)) which leads to hypothyroidism.
2. Focal Segmental Glomerulosclerosis (FSGS)
The second common type of nephrotic syndrome but in UP To Date UTD it is
considered as the third type after MPGN as the doctor said.

Is found in about 7-15% of patient with Nephrotic syndrome.

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Main points

Complications Of Nephrotic syndrome:

Why edema
happens in patients
with Nephrotic
syndrome?

What are the

underlying causes
of renal
impairment?

What is the clinical

picture of edema?

How is edema
examined?

Edema
1. Causes : Edema happens because of protein loss which leads to decrease in
the vascular Oncotic pressure. There is another cause of Edema which is renal
impairment that happens usually in children because of decrease osmotic pressure
that leads to kidney hypo perfusion and so fluid retention takes place as a result
of hypo perfusion, in those patients the more is the fluid retention the more severity
of the edema is. (Usually the intravascular pressure in children is good and this is
explained by the second cause -Renal Impairment-).
Why renal impairment happen? Because of:
1- Renin-Angiotensin system activation.
2- Sodium and fluid retention.
2. Character: Generalized swelling starts in the morning with puffiness around the
eyes and predictable ascites and as the day passes the edema will be more in the
dependent locations of the body e.g. lower limbs, Genitalia, Hands and sacrum
"esp. in babies", OTHER SPACES WHERE FLUID CAN ACCUMULATE are called 3rd
spaces which include scrotum, genitalia, abdomen "Ascites" and pleura "pleural
effusion".
Notes:
-Because of the Ascites some patients might have inguinal or umbilical hernia.
-Some patient might have intestinal edema which causes diarrhea accompined by
abdominal pain and poor absorbtion.
3. Type: It is Pitting edema, you examine it by applying a good pressure for
30 seconds by your finger against a hard bony structure "usually the shaft of the
tibia" and if it is present you will have a dimple -small indentation on the body-.

What are the

causes of the
hypercoagulable
state in patients
with nephrotic
syndrome?

Hypercoagulable state :
due to loss of Anti-thrombin3, increase activity of the other factors and
thrombocytosis in addition to activation of proteins C and S and increase the
production of coagulation cascade's factors because of increase production by the
liver, the main manifestation of the hypercoagulable state is Thromboemblism and
it could take place anywhere in the body e.g. sagittal sinus in the brain and the
patient may come with irritability, another manifestation is DVT here the patient
comes with gross Hematuria and sometimes renal impairment.

What is the vaccine

that is given to
Nephrotic
syndrome patients?

Increase risk of infections

Due to loss of Immunoglobulins and complement proteins in the urine, usually the
infection is caused by encapsulated microorganisms and so Pneumocoocal vaccine is
indicated and you have to take any sign seriously because it may be an indicator
of underlying infection.

PAGE 6
Main points

What are the risk

factors for acute
renal failure in
Nephrotic
syndrome patients?

Hypertension
Change in pharmacodynamic of many drugs due to loss of drug binding proteins
and albumin.
Acute renal failure "prerenal" and it could be Drug induced ((e.g. in volume
depleted patients if you give NSAIDs, Vancomycin or any nephrotoxic medications could
end with Acute renal failure)), again Acute renal failure may happen in those patients
with rabidly progressive Glomerulonephritis like in HSP patients, not only that but
acute renal failure could happen in patients with UTI, obstruction nephropathy or those
with Thrombosis (Renal vein thrombosis).
Investigations:
1. Serum albumin.
2. Lipid profile.
3. KFT Kidney function Test-.
4. CBC.
5. Hb can be high due to concentration effect and can be low due to overfill
effect
6. Electrolytes.
Acute Management:

When albumin
administration is
recommended?

Is it safe to give
hyperosmolar fluids
to patient with
renal failure?

It is supportive management include:

- Salt / fluid restriction.
- Diuretics
- Albumin ((only in certain conditions e.g. Circulatory collapse, Hypotension, poor
capillary refill, Cold extremities, poor perfusion and renal impairment "increase
urea")).
- Treatment of any complications.

Be Careful: If you give a hyperosmolar fluid to a renal failure patient he

could end up with pulmonary edema and your patient will need a ventilator.

It is important for the patient to be on high protein diet in order to

compensate for the ongoing loss.

It is important not to give any live vaccines while you are treating your patient
with steroids (except patients with congenital nephritic syndrome).
Initial therapy:

st

What is the 1 line

treatment in
patients with
Nephrotic
syndrome?

If it is a pure Nephrotic syndrome with normal KFT and no hypertension then start
the treatment initially with steroids.
If it is not a pure Nephrotic syndrome with abnormal KFT, hypertension, or any
abnormal findings ((Gross Hematuria, increase in the amount of casts and high
creatinine)) then you should do Renal Biopsy then give steroids for your patient and don't
wait for the result of the renal biopsy.

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Main points

Does steroid
treatment result in
complete remission
of the nephrotic
patients?

We start Steroid Treatment with a dose of 60mg/m2 for 6-8 weeks then we start
tabering slowly with a new dose of 40mg/m2 for another 4 weeks then I start
decreasing the dose by 0.5mg/kg every 2 weeks.
90% of the patient respond to steroids in pediatric ages.
2/3 of those who respond to steroids have recurrent illness "relapse".
1/3 of those who respond to steroids will improve completely.
Note : If the patient suffer from recurrence rate of 2 times(or more) / 6 months then
you has to shift to the 2nd line of treatment because as you know steroids have many
complications and it is contraindicated to give more than 2 steroid courses/6 months.
Note: small percent of the patients with minimal change don't respond to steroids, this
could be because the tissue you gain by the biopsy is an intact one and you have missed
an underlying etiology just because it is not in the biopsy.
If your patient is not responding to steroids you should think about other etiologies
such as FSGS

If your patient has

3 episodes of
Nephrotic
syndrome during
the last 6 months
how would you like
to treat him?

SECOND & THIRD LINE TREATMENT: those are used in relapsing cases in order to
stabilize the patient and to avoid the use of steroids, but even if the patient relapsed
while he is on the 2nd or the 3rd line treatment you have to give him steroids
The first drug to be used as second line treatment is cyclophosphamide which is used in
patients with frequent relapses who are not steroid dependents, on the other hand steroid
dependent patients are treated with cyclosporine and if it is not effective then use
Tacrolimus.
Note:
* Cyclophosphamide is Antineoplastic Agent, Alkylating Agent Antirheumatic and Miscellaneous.
*Cyclosporine is a lipophilic cyclic peptide while Tacrolimus is a macrolide antibiotic. Both drugs
possess similar suppressive effects on cell mediated and humoral immune responses.
*Both Drugs bind with high affinity to a family of cytoplasmic proteins present in most cells:
cyclophilins for cyclosporine; and FK binding proteins for tacrolimus. The drug-receptor complex
specifically and competitively binds to and inhibits Calcineurin(a calcium and calmodulin
dependent phosphatase), This process inhibits the translocation of a family of transcription factors,
leading to reduced transcriptional activation of early cytokine genes for IL-2, tumor necrosis
factor alpha (TNF-alpha) IL-3, IL-4, CD40L, granulocyte-macrophage colony-stimulating factor,
and interferon-gamma.

Levamisole (Antiparasitic) have been used long time ago but now this drug isnt used
any more.
Mycophenolate Mofetil (MMF) has been used but Limited data exist about this drug,
overall it is considered as a good medication.
B-cells supressors help improving some of the cases that are nonresponsive to other
medications.

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Main points

In case of
Nephrotic
syndrome, What do
we mean by
Remission, Relapse,
frequent relapse,
steroid dependent
and non-steroid
dependent?

If your Nephrotic
patient has scrotal
edema what your
next step should
be?

What is written at
the end of most
lectures?

IMPORTANT DEFINITIONS:
- Remission: means that urine proteins go back to normal (Remission confirmed
only if proteins were measured for 3 continuous days).
- Relapse: means that urine proteins goes back again to the nephrotic Range
after improvement -remission-. (Relapse confirmed only if proteins were measured
for 3 continuous days)
- Frequent relapses: 2 relapses/6 months OR More than 3 relapses/ year.
- Steroid dependent: 2 Relapses while tapering steroids OR relapse within 2
weeks after completion of steroid therapy.
- Steroid resistant: fail to get remission within 4-6 weeks of receiving steroids.
WHEN TO START THINKING ABOUT SOMETHING ELSE ??
- Frequent relapses.
- Non-responsive to steroids.
- Requirement for higher dose of steroids.
KEY POINTS:
- Minimal change disease rarely progress to renal failure and usually those
patients resolve at the puberty but unfortunately they will have the side effects of
the steroid therapy.
- Nephrotic syndrome is a disease of protein leakage (mainly albumin) outside
the body.
- Fluid retention is the main clinical presentation in Nephrotic syndrome patients
and the excess fluids are managed by diuretics only and usually no need for
albumin or salt restriction.
- The Definite Diagnosis is only done by Biopsy and no way to diagnose the
definite type of Nephrotic syndrome clinically.
- (Important) Whenever your patient has scrotal edema you have to give
albumin.

THE END
If you have any feedback please let me know

Moh'd olimat

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(( ,
)) ((

,

WWW.SHIFA2006.com

Correction
1-Fluid & electrolyte therapy
Dr.A.Chishti
http://www.scribd.com/doc/14581231/Clinical-Pediatrics-Lectures-or-Tutorial
Fluid and electrolytes
cc = cubic centimeter = milliliter All the concentrations of fluids given to the patients can be (and they
usually) little more or less than the calculated numbers (approximations) because companies prepare
fluids with specific concentrations, and we choose the most appropriate one.
Maintenance fluid Amount needed every day (for compensation and to burn calories) It includes
sensible and insensible water loss Sensible: e.g. urine and stools Insensible: e.g. respiration
(evaporation) and sweating We calculate it by any of the two methods below:
(1) The first method: First 10 kg 100 cc/Kg Second 10 kg 50 cc/Kg For any one kg above 20 20 cc/KG
For example: child with 20 kg weight, we give him 1500 cc. For first 10 kg we give him 100 cc/kg, so
we give him a total of 1000 cc for the first 10 kg of his weight. For the rest, which is 10kg
(2010=10kg) we give him 50cc/kg, so we will give him 500cc for the second 10kg. The total will be
1500cc (1.5L) for the 20 kg. Another example: 37 kg we give him 1840cc As in previous example,
first 10 kg 1000cc Second 10 kg 500 cc Then we will have 17kg (37-20=17kg). From the rule, for any
single kg after 20kg we give 20 cc/kg. So, for the 17 kg 17 X 20 = 340 ml. The total will be
340cc+1500cc=1840cc Another example: 45 kg child 2000cc
(2)The second method: Is by using the surface area to calculate the maintenance fluid. This method is
rarely used and we dont use it usually. Maintenance fluid =1600cc/m2/day pg 4 of lecture

(160 cc/m2/hr)