MCD causing approximately 77% of cases and focal segmental
glomerulonephritis (FSGS) and MPGN the majority of the remaining
occurrences. Children typically present between the ages of 2 and 6 years,
and the reported ratio of boys to girls who are diagnosed at a younger age is
as high has 2:1. The gender ratio is closer to 1:1 in those who present later
in childhood or as adolescents.

Goals of Treatment
Many children with nephrotic syndrome present to the ED with signs of
fluid overload. Initial management should focus on improving fluid balance
while monitoring for signs of intravascular volume depletion. Children
should also be assessed for underlying complications of nephrotic syndrome
such as infection and thrombosis. If a diagnosis of nephrotic syndrome has
not been established in the past, an initial workup for potential underlying
causes may be initiated.

Clinical Considerations
Clinical recognition. Nephrotic syndrome results when there is increased
permeability across the glomerular filtration barrier. It is characterized by
hypoproteinemia, edema, hyperlipidemia, and massive proteinuria
exceeding 50 mg/kg/day. Hypertension may be present, especially in the
setting of FSGS, but is often absent in MCD. Edema, often the most
noticeable clinical manifestation of nephrotic syndrome, is the result of
excessive salt and water retention. Periorbital edema is often the initial
finding and may be misdiagnosed as signs of allergy. The associated edema
is gravity dependent and therefore will vary in location based on patient
position and activity. Upon awakening, edema may be more marked in the
face and then shift to the lower extremities with ambulation. It may also be
notable in the scrotal or vulvar regions. Other complications of third
spacing, such as ascites, pulmonary edema, and pleural effusions, may also
occur.

Although children with nephrotic syndrome and edema have total body
sodium and water excess, some will present with evidence of intravascular
depletion. This is more likely to occur in those with severe
hypoalbuminemia and will be exacerbated by diuretic use, gastrointestinal


losses, and restricted intake. Signs of decreased effective circulating volume
include tachycardia, peripheral vasoconstriction, and oliguria.
In addition to overall volume excess with or without intravascular
depletion, complications resulting from nephrotic syndrome include
infection and thromboembolism. Children with nephrotic syndrome are at
increased risk of developing serious bacterial infection, particularly
infections with encapsulated bacteria, because of urinary losses of
immunoglobulins and alternative complement pathway factors B and D.
Children who are treated with immunosuppressive agents will have
additional risk. Furthermore, ascites and pleural effusions increase the risk
for peritonitis, pneumonia, and empyema. Other potential complicating
infections include sepsis, meningitis, cellulitis, urinary tract infection, upper
respiratory tract infection, and severe acute gastroenteritis.
Thromboembolic complications are reported in 2% to 9% of children
with nephrotic syndrome and may occur in either the arterial or venous
circulation. The actual incidence may be higher, however as
thromboembolic events may be asymptomatic. The risk may be higher in
children with steroid-resistant disease. Nephrotic syndrome results in a
hypercoagulable state due to urinary losses of antithrombin III, protein S,
and plasminogen and increased circulating fibrinogen, factors V and VII as
well as increased platelet activation. Though many embolic events are
silent, cerebral venous thrombosis, pulmonary embolism, and renal vein
thrombosis may result in significant morbidity. Though a much less
frequent occurrence in children than in adults with nephrotic syndrome,

renal vein thrombosis should be suspected in cases of sudden-onset
macroscopic hematuria and flank pain.
Triage considerations. Children with nephrotic syndrome may present
acutely ill with signs and symptoms of fluid overload. Patients may require
support of lung function due to pulmonary edema. Hypertension, if present,
can be symptomatic and may require emergent management. They are at
risk for serious bacterial infections as well as both venous and arterial
thrombosis and may require emergent evaluation and treatment for these
conditions. Other patients may present with mild symptoms related to
edema and will be managed with gentle diuresis with fluid and salt
restriction.


Clinical assessment. The initial assessment of a child with nephrotic
syndrome should focus on the adequacy of intravascular volume and
perfusion, respiratory status, and evaluation for evidence of complications
such as infection. There should be a thorough assessment of recent fluid
balance, with specific inquiries to diuretic use, urine output, and
gastrointestinal losses. As some patients with nephritis will have
concomitant nephrotic syndrome (secondary nephrotic syndrome), accurate
measurement of blood pressure should be documented to screen for
associated hypertension.
Laboratory investigation should include confirmation of nephrotic
syndrome, identification of associated electrolyte abnormalities, and an
evaluation for possible underlying etiologies, if clinically indicated by
evidence of systemic disease. A serum albumin of less than 2.5 g/dL is
suggestive of nephrotic syndrome. A freshly obtained urine sample should
confirm heavy proteinuria by dipstick and be inspected for the presence of
macroscopic hematuria, which may suggest glomerulonephritis. Nephrotic
range proteinuria in children is defined as protein excretion greater than 50

mg/kg/day or 40 mg/m2/hr, though this would depend upon a timed 24-hour
urine collection, which is prone to inaccuracies and not feasible in the ED.
Alternatively, a urine protein to creatinine ratio can be obtained on a spot
urine sample to quantify the degree of proteinuria. A normal ratio is less
than 0.5 in children 6 to 24 months and less than 0.2 in older children and
adults. Generally, a ratio more than 2 to 3 is consistent with nephrotic range
proteinuria. Idiopathic nephrotic syndrome is typically associated with
bland urine sediment.
Serum electrolytes may reveal hyponatremia secondary to decreased
intravascular volume and stimulation of ADH release. Hyponatremia in the
edematous child does not reflect total body sodium depletion but water
excess that is greater than sodium excess. Renal function studies may be
abnormal and reflect decreased intravascular volume or the underlying renal
disease. Complete blood cell counts may demonstrate elevated hemoglobin
and hematocrit due to hemoconcentration. Hyperlipidemia including
elevated total serum cholesterol, triglycerides, and total lipids is typical.
Studies to distinguish the cause of nephrotic syndrome should be
considered based on the patient’s presentation. Serum complements may
identify disorders associated with complement consumption such as


postinfectious glomerulonephritis, MPGN, and lupus nephritis. Additional
studies to be considered include HIV, hepatitis B and C serologies in highrisk patients, and serum antinuclear antibodies, especially in children with
symptoms of SLE or aged 10 years or more.
Management. Given that there are two major processes leading to edema
in nephrotic syndrome, arterial underfilling due to low oncotic pressure and
primary renal sodium retention, management of fluid excess requires
careful attention to the underlying causes. Diuretic therapy would be
effective in reducing edema and indicated if the primary process is renal
sodium retention. However, if hypoalbuminemia leads to decreased plasma

volume via movement of fluid from the vascular space to the interstitium,
diuretic therapy may aggravate arterial underfilling. As it may be difficult to
determine intravascular volume in patients with nephrotic syndrome,
clinical characteristics that may predict intravascular volume status include
GFR and serum albumin level. Patients with decreased vascular volumes
and severe hypoalbuminemia may require albumin infusions in conjunction
with diuretics in order to maintain arterial filling pressures. Children who
present with severe edema should be admitted and may be treated with
furosemide and albumin (e.g., 25% albumin) to achieve diuresis. Albumin
(0.5 to 1 g/kg) infused over 4 hours followed by one to two doses of
furosemide (0.5 to 1 mg/kg/dose) should result in fluid mobilization.
Providing albumin will bolster the intravascular oncotic pressure and
safeguard against volume depletion during fluid mobilization.
Once the patent is stabilized, a plan for sodium and fluid restriction
should be made. Optimally, children are restricted to approximately 2 to 3
mEq/kg/day of sodium or up to a maximum of 2,000 mg/day in older
children and adolescents. Water restriction should be initiated given the
release and action of ADH resulting in dilutional hyponatremia. Admission
for close volume management should be strongly considered if evidence of
hypovolemia is apparent at presentation or uncontrolled fluid loss is
anticipated (i.e., gastroenteritis) given the risk for thromboembolic
complications and prerenal kidney injury.
Children with nephrotic syndrome who are hemodynamically stable
should be started on daily prednisone at 2 mg/kg or 60 mg/m2 after
consultation with a nephrologist. If they do not require hospital admission
for close fluid balance monitoring, they should be followed closely as an