Everything You Need to Know About Nephrotic Syndrome in One Case

Lucile Packard Childrens Hospital

Pediatric Residency Training Program
Renal Learning Topics for Residents
Scott Sutherland, MD
CASE PRESENTATION, CLINCAL QUESTIONS, AND BOARDS STYLE QUESTIONS
A 6 year old boy with no significant medical history presents to your office with a one week
history of eye swelling. When you see him in your office, he has moderate peri-orbital edema
but appears to be in high spirits. He is afebrile and has a normal heart rate and blood pressure.
The parents report that they just brought a brand new kitten home and they wonder if perhaps
their son could have an allergy to cats. You think this is quite likely and prescribe cetirizine and
ask them to return in a week for a follow up visit.
QUESTION 1: Youre kidding me right? Theres no way this kid gets out of my office without
me checking his urine for protein. I mean, come on, the nephrotic-kid-presenting-with-eyeswelling-and- the-diagnosis-being-missed is like the biggest clich ever. Dont even think
about trying to sneak this one by me. Be honest, do kids with nephrotic syndrome ever present
in any other way?
Answer 1: It is possible that this is the most overused clinical scenario in the history of
medicine. From the standpoint of the Boards, chances are you wont see a question with a
nephrotic patient presenting this way; more likely, youll get a question where they tell you the
boy has nephrotic syndrome and then ask you a question about treatment/complications/
epidemiology. But dont worry, youll be ready for them because youre going to keep reading
this case. In practice, some kids with nephrotic syndrome actually do present this way and
occasionally the diagnosis is initially missed. Pediatricians see one case of nephrotic syndrome
every 10 years (the incidence is 2-7 per 100,000 patients) and one case of allergies every
morning. Thats just the way it goes. Kids can also be brought to medical attention because their
tummy, hands, feet, scrotum, or vulva seems swollen, their shoes dont fit, or their socks leave
indentations. If they have been nephrotic for quite some time, pleural effusions and respiratory
distress can be present. Sometimes parents will report the child has foamy urine or is peeing less.
When the boy returns in a week, he now has swelling of his abdomen, feet, hands, scrotum, and
legs. He remains afebrile and although his blood pressure is 102/68, his heart rate is 179. He
also has gained 8 pounds over the week.
QUESTION 2: What is this boys volume status? What is this boys intravascular volume
status?
Answer 2: This boy is clearly hypervolemic, but is acting intravascularly depleted. Although
kids with nephrotic syndrome become fluid overloaded, they are usually intravascularly dry.
The massive proteinuria leads to hypoalbuminemia, resulting in markedly decreased
intravascular oncotic pressure and leakage from the intravascular space into the interstitial space.
Tachycardia is quite common.

You diagnose the boy with idiopathic nephrotic syndrome and refer him to a nephrologist for
further evaluation and management.
QUESTION 3: Which of the following are components of the nephrotic syndrome?
A.
B.
C.
D.
E.
F.
G.

Hypoalbuminemia
Nephrotic Range Proteinuria
Gross Hematuria
Microscopic Hematuria
Edema
Hyperlipidemia
Hypertension

Answer 3: The four components of nephrotic syndrome are:

1. Nephrotic range proteinuria
2. Hypoalbuminemia (can often be <1g/dL)
3. Hyperlipidemia
4. Edema.
Nephrotic range proteinuria is defined as a spot protein/creatinine ratio above 2 or a 24 hour
protein excretion greater than 1g/m2/24hrs. Gross hematuria, hypertension and renal failure
comprise the classic triad seen in glomerulonephritis. It is important to remember that severe
cases of glomerulonephritis can be complicated by nephrotic range proteinuria and even the
entire nephrotic syndrome. However, this case and the associated discussion are focused on
idiopathic, isolated nephrotic syndrome. Gross hematuria, renal failure, hypertension, and
abnormal lab results (such as low C3 and C4) are all clues that a child has glomerulonephritis or
a diagnosis other than idiopathic nephrotic syndrome. Microscopic hematuria, however, can be
seen in 20-25% of patients with nephrotic syndrome.
QUESTION 4: What is the most likely cause of this boys nephrotic syndrome?
A.
B.
C.
D.
E.

FSGS
Minimal Change Disease
Cetirizine
Membranous Nephropathy
MPGN

Answer 4: B. Minimal change disease (MCD) is the most common diagnosis in children with
nephrotic syndrome and at times is used synonymously with it (incorrectly). It accounts for 3
out of 4 cases of nephrotic syndrome, including 90% of cases in children less than 10 years of
age and 50% of cases in children greater than 10 years of age. There are really only 2 other
causes of idiopathic nephrotic syndrome in children focal segmental glomerulosclerosis
(FSGS) and membranous nephropathy. In children, most nephrotic syndrome that is not MCD is
FSGS, making idiopathic membranous nephropathy exceedingly uncommon. If present,
membranous nephropathy can be secondary to lupus, medications, hepatitis B and C, and

malignancy. FSGS looks a lot like MCD, however, it tends to present in older children, is often
associated with renal failure and hypertension, and tends to be steroid resistant (20% of patients
with FSGS are steroid responsive). FSGS recurs following transplantation 10-25% of the time.
In infants (less than 12-18 months of age) you need to worry about congenital nephrotic
syndrome (CNS) and diffuse mesangial sclerosis (DMS). CNS, by definition, presents in the
first 3 months of life. More commonly, however, it is diagnosed within the first month when the
child develops anasarca. This is especially true for the Finnish type of CNS. DMS tends to
present later (6-18 months of age) but clinically presents just like CNS or MCD. Like CNS and
unlike MCD, DMS is totally refractory to immunosuppression. Unlike CNS and MCD, DMS is
often complicated by fairly marked renal failure.
Additionally, it is important to remember that there are a handful of mixed nephritic/nephrotic
diseases than can be complicated by nephrotic syndrome. These include membranoproliferative
glomerulonephritis (MPGN), proliferative glomerulonephritis (IgA/HSP, post infectious
glomerulonephritis), lupus, and pauciimmune glomerulonephritis such as Wegners and
microscopic polyangiitis.
QUESTION 5: Back to our boy. How should this patient with idiopathic nephrotic syndrome
initially be managed?
Answer 5: The cornerstone of management of idiopathic nephrotic syndrome is steroid therapy.
The most commonly used regimen is as follows: 6 weeks of prednisone at a dose of 2mg/kg/day
followed by 6 weeks of prednisone at a dose of 1-1.5mg/kg/every other day. After the complete
12 week course, some practitioners stop cold turkey and some will taper the steroids over 2-4
weeks. While nephrotic, patients should be fluid and salt restricted. Usually we restrict fluid to
between 500mL (little kids) and 1000mL (bigger kids) and recommend that kids eat a no salt
added diet. Once the nephrotic syndrome is put into remission, the restrictions can be lifted.
QUESTION 6: Should he be admitted or can this be managed as an outpatient?
Answer 6: These children can often be managed as outpatients. However, it does require that the
parents adhere to the fluid/salt restriction and administer a sort of yucky tasting medicine twice
daily (usually the 2mg/kg/day is divided BID). If the child has been nephrotic for an extended
period of time, often there is significant bowel wall edema which hampers absorption of the oral
steroid, leading to failure of outpatient therapy.
Many pediatricians and family members are uncomfortable with the overall anasarca and
management and it is always, always reasonable to admit these patients. Definitive indications
for admission include: fever, infection, respiratory distress, hypertension, severe intravascular
volume depletion or marked hemoconcentration, vomiting or inability to administer oral
medications, physical discomfort, lack of response to approximately one week of oral therapy,
and concern for thrombosis.
If admitted, steroid therapy is usually given intravenously (solumedrol 1mg/kg/BID). Often a
PICC is required due to prolonged IV use and frequent lab draws. Children who are admitted are

often given intravenous 25% albumin to normalize their serum albumin level. This allows 3rd
spaced fluid to return to the intravascular space. Furosemide is given concurrently to aid diuresis.
This approach should only be used once you are certain the patient is diuretic responsive.
Mobilization of 3rd spaced fluid into the intravascular space can lead to pulmonary edema and
hypertension if the fluid is not eliminated via diuresis. Due to this risk, if you have not done so
already, you should consult with a nephrologist before deciding to administer 25% albumin.
Occasionally, children who fail to respond to oral/IV prednisone at a dose of 2mg/kg/day will
receive a short course of solumedrol at a much higher pulse dose of 30mg/kg/day (max
1000mg). This is really reserved for cases that are steroid resistant, especially challenging, or
due to FSGS.
QUESTION 7: True or False? A kidney biopsy is clearly indicated at presentation.
Answer 7: False. Most children with nephrotic syndrome are not biopsied at presentation
because most nephrotic syndrome is due to minimal change disease. The main indication for
biopsy is steroid resistance (persistent proteinuria after 4-6 weeks of steroid therapy). Some
practitioners also biopsy patients who are frequently relapsing or steroid dependent before
transitioning them to an alternative immunosuppressant. Some practitioners will perform
biopsies in older children (above age 10-12 years) at presentation due to the greater incidence of
FSGS. However, as responsiveness to steroid therapy is probably more important prognostically
than the actual diagnosis, we tend to give all patients with nephrotic syndrome a trial of steroid
therapy before performing a kidney biopsy. Children who have a mixed nephritic/nephrotic
picture usually undergo biopsy as do children who present atypically.
Here are some typical biopsies of minimal change disease, FSGS, and membranous nephropathy,
the three diseases that cause idiopathic nephrotic syndrome in children:
MINIMAL CHANGE DISEASE:
Light Microscopy appears normal. Electron Microscopy reveals effacement of the podocyte foot
processes (B). A normal electron micrograph of podocyte foot processes is shown in panel (A).
Instead of separate, all the foot
processes have become fused

FSGS
On light microscopy, the lesions are both focal (not all glomeruli affected) and segmental (Only
a portion of the affected glomerulus is sclerosed). Compare the image to the normal glomerulus
on the right.
FSGS Lesion

Membranous Nephropathy:
Compare the lobulated appearance of the glomerulus below to the normal glomerulus above.
Silver staining (second image right) is the technique usually used to diagnose membranous
nephropathy. Silver stains the glomerular basement membrane, as finger-like projections of
GBM can be seen growing around membranous deposits (arrow).

The patient is intravascularly dry and you worry about both compliance and follow up so the
patient is admitted to the hospital for initial management. You received a thorough discharge
summary from one of the outstanding Packard residents which states that the boy went into
remission after 5 days of IV steroid therapy and was discharged to complete a course of steroids.

He will follow up regularly with the nephrology service. They ask his parents to dip his urine
daily and call immediately should his first morning urine have 1+ or greater proteinuria for three
consecutive days.
You see the patient every couple of months and follow up more frequently by phone to make
sure he remains in remission and healthy. About a year and a half later, the boy returns for his
annual well child check and, as you review his medications, you note that he is now receiving
tacrolimus and he had previously been on cyclophosphamide for 3 months.
QUESTION 8: Why might this child have received tacrolimus and cyclophosphamide?
Answer 8: Nearly 90% of children with nephrotic syndrome are steroid responsive and respond
to steroid therapy within 4 weeks. However, over half relapse frequently (2x in 6mo or 4x in a
year) or are steroid dependent (relapse occurs during taper phase of prednisone therapy).
Following the initial 12 week course of prednisone therapy, approximately 1/2 will enjoy a
sustained remission, 1/3 will relapse frequently, 1/4 will be steroid dependent, and the remainder
will prove to be steroid resistant.
Frequently relapsing and steroid dependent patients are likely to require steroid therapy for a
large portion of the year since each relapse is treated with a 4-6 week course of steroids. A
common regimen used to treat individual relapses is to start prednisone at 2mg/kg/day until the
childs urine is dip negative for protein for three consecutive days. Then the child receives
1mg/kg/every other day for three weeks. Finally, the prednisone is weaned off over the next 1-2
weeks.
Steroid side effects are well documented and debilitating. Although patients with minimal
change disease classically outgrow their disease, the entire disease course can be 10-15 years if
they are diagnosed early in childhood. Therefore, patients who are frequently relapsing or
steroid dependent are often placed on steroid sparing agents.
Steroid sparing agents include cyclosporine, tacrolimus, cyclophosphamide, and mycophenolate
mofetil. Cyclosporine, tacrolimus, and MMF merely replace the steroid therapy they are
administered chronically until the child grows out of the disease. Cyclophosphamide can
actually cure the disease, or at least result in an extended period of remission without the need
for medications. Following a 3 month course of cyclophosphamide therapy, approximately 3565% of children will remain in remission at 5 years and approximately 25% will remain in
remission at 10 years. Some children will stay in remission on low dose alternate day
prednisone, which is an acceptable regimen as well. Patients who are frequently relapsing tend
to be more responsive to these agents than patients who are steroid dependent. Practice varies as
to which is used as a first line sparing agent.
Some patients will be defined as steroid resistant (failure to respond to 4 weeks of 2mg/kg/day of
prednisone therapy). These patients with nephrotic syndrome carry the worst prognosis. They
are less likely to respond to any of the aforementioned immunosuppressants, are more likely to
experience the complications of chronic nephrosis, and are more likely to progress to end stage
renal disease. Tacrolimus, cyclosporine, and MMF are often trialed, both alone and in

combination, in these patients. Because they are less likely to respond to cyclophosphamide, the
potential risks start to outweigh the potential benefits and cyclophosphamide is not often used
first line in these patients. These patients can be treated with the Tune-Mendoza protocol or a
variation thereof. This protocol uses pulse dose solumedrol (30mg/kg up to 1000mg max),
which is administered intravenously. The protocol begins with the solumedrol being
administered thrice weekly for two weeks followed by weekly administration. Although the
original protocol administered solumedrol at increasing intervals for up to 18 months, many
practitioners use a shorter regimen of 2-6 months.
QUESTION 9: Which of the following are complications of nephrotic syndrome?
1. Peritonitis
2. Pleural Effusions
3. Pulmonary Edema
4. Thromboembolism
A. 2 and 3
B. 1, 2, and 3
C. 2, 3, and 4
D. 1, 2, and 4
Answer 9: D. Peritonitis can occur spontaneously if ascites present. When present, spontaneous
bacterial peritonitis is usually due to encapsulated organisms (due to opsin loss). Patients with
nephrotic syndrome are at increased risk for all types of infections due to loss of
immunoglobulins. Fever in a child with active nephrotic syndrome requires urgent medical
attention and they should be evaluated immediately. Pleural effusions can occur if
hypoalbuminemia and fluid overload is severe. They can be quite challenging to mobilize.
Thromboembolism is due to loss of natural anticoagulants, hemoconcentration, and
thrombocytosis. One option is to provide prophylaxis with aspirin. Actual thrombosis needs to
be acutely treated with anticoagulants. I have always been taught that pulmonary edema actually
does not occur; this has to do with differential permeability between pulmonary and peripheral
capillaries. However, you can certainly cause iatrogenic pulmonary edema if you give too much
albumin, too fast, without enough lasix.
SUMMARY AND LEARNING POINTS
Nephrotic syndrome is defined as the presence of nephrotic range proteinuria (urinary
protein/creatinine ratio >2mg/mg), hypoalbuminemia, edema, and hyperlipidemia
The three diseases that can cause idiopathic nephrotic syndrome in children are minimal
change disease (far and away the most common), focal segmental glomerulosclerosis, and
membranous nephropathy.
Congenital nephrotic syndrome and diffuse mesangial sclerosis need to be considered in
infants with nephrotic syndrome.

 Several types of glomerulonephritis can be accompanied by nephrotic range proteinuria or the

entire nephrotic syndrome. These cases tend to be marked by gross hematuria, renal
insufficiency, hypertension, and other laboratory abnormalities.
The initial management of these children includes steroid therapy, fluid and salt restriction.
Long term management of these children can include low dose alternate day steroid therapy,
tacrolimus, cyclosporine, cyclophosphamide, and/or MMF.
These children are at risk for infections, peritonitis, thrombosis, and respiratory compromise
when actively nephrotic.
SUGGESTED READING

1. Eddy A, Symons J. Nephrotic syndrome in childhood. The Lancet 2003;362(9384):629639.

2. Gipson DS, Massengill SF, Yao L, et al. Management of Childhood Onset Nephrotic
Syndrome. Pediatrics 2009;124(2):747-757.