NEPHROTIC SYNDROME (NS)

Nelson
Treatment.
Children with the first episode of nephrotic syndrome and mild to moderate edema may be managed as
outpatients. Affected children may attend school and participate in physical activities as tolerated. The
pathophysiology and treatment of nephrotic syndrome should be carefully reviewed with the family to enhance
their understanding of their child's disease. Sodium intake should be reduced by the initiation of a low sodium diet
and may be normalized when the child enters remission. Although there are no data to support their safety or
efficacy, oral diuretics are used by many clinicians for children with nephrotic syndrome. Because of the possibility
of increasing the risk of thromboembolic complications, diuretic use should be judicious and should be carefully
supervised by a pediatric nephrologist.
Children with severe symptomatic edema, including large pleural effusions, ascites, or severe genital edema,
should be hospitalized. In addition to sodium restriction, fluid restriction may be necessary if the child is
hyponatremic. A swollen scrotum may be elevated with pillows to enhance the removal of fluid by gravity. Diuresis
may be augmented by intravenous administration of chlorothiazide (10?mg/kg/dose every 12?hr) or metolazone
(0.1?mg/kg/dose bid) followed by furosemide 30?min later (1–2?mg/kg/dose q 12?hr).
Intravenous administration of 25% human albumin (0.5?g/ kg/12?hr) is often necessary when this potent
combination is used. Such therapy mandates close monitoring of volume status, serum electrolyte balance, and
renal function. Symptomatic volume overload, with hypertension and heart failure, is a potential complication of
parenteral albumin therapy.
Children with onset of nephrotic syndrome between 1 and 8 yr of age are likely to have steroid-responsive minimal
change disease; therefore, steroid therapy may be initiated without renal biopsy. Children with features that make
minimal change disease less likely (hematuria, hypertension, renal insufficiency, hypocomplementemia, age < 1 yr
or > 8 yr) should be considered for renal biopsy before treatment.
In children with presumed minimal change disease, prednisone should be administered (after confirming a
negative PPD test) at a dose of 60?mg/m2 /day (maximum daily dose, 80?mg), divided into two to three doses for
at least 4 consecutive weeks. There is some evidence that an initial 6 wk course of daily steroid treatment may lead
to a lower relapse rate, although the frequency of steroid-induced side effects is significantly higher. Eighty to 90%
of children will respond to steroid therapy (urine trace or negative for protein for 3 consecutive days), with the
median time to remission of 10 days. The vast majority of children who will respond to prednisone therapy will do
so within the first 4 wk of treatment.
After the initial 4–6 wk course, the prednisone dose should be tapered to 40?mg/m2 /day given every other day as
a single morning dose. The alternate-day dose is then slowly tapered and discontinued over the next 2–3 mo.
Children who continue to have proteinuria (2+ or greater) after 8 wk of steroid therapy are considered steroid
resistant, and a diagnostic renal biopsy should be performed.
Many children with nephrotic syndrome will experience at least one relapse (3–4+ proteinuria plus edema).
Although relapse rates of 60–80% have been noted in the past, the relapse rate in children treated with longer
initial steroid courses may be as low as 30–40%.
Relapses should be treated with daily divided-dose prednisone at the doses noted earlier until the child enters
remission (urine trace or negative for protein for 3 consecutive days). The prednisone dose is then changed to
alternate-day dosing and tapered over 1–2 mo.
A subset of patients will relapse while on alternate-day steroid therapy or within 28 days of stopping prednisone
therapy. Such patients are termed steroid dependent. Patients who respond well to prednisone therapy but
relapse four or more times in a 12-mo period are termed frequent relapsers. Children who fail to respond to
prednisone therapy within 8 wk are termed steroid resistant.

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Steroid-dependent patients, frequent relapsers, and steroid- resistant patients may be candidates for alternative
agents, particularly if the child suffers severe corticosteroid toxicity (cushingoid appearance, hypertension,
cataracts, and/or growth failure). Cyclophosphamide has been shown to prolong the duration of remission and to
reduce the number relapses in children with frequently relapsing and steroid-dependent nephrotic syndrome. The
potential side effects of the drug (neutropenia, disseminated varicella, hemorrhagic cystitis, alopecia, sterility, and
increased risk of future malignancy) should be carefully reviewed with the family before initiating treatment. The
dose of cyclophosphamide is 2–3?mg/kg/24?hr given as a single dose, for a total duration of 8–12 wk. Alternate-
day prednisone therapy is often continued during the course of cyclophosphamide administration. During
cyclophosphamide therapy, the white blood cell count must be monitored weekly and the drug withheld if the
count falls below 5,000/mm3 .
An additional option for the child with complicated nephrotic syndrome is high-dose pulse methylprednisolone.
Methylprednisolone is usually given as a 30-mg/kg bolus (maximum 1,000?mg), with the first 6 doses given every
other day, followed by a tapering regimen for periods up to 18 mo. Cyclophosphamide may be added to this
regimen in selected patients.
Prolonged administration of cyclosporine (3–6?mg/kg/24?hr) has also been effective in maintaining a prolonged
remission in children with nephrotic syndrome and is useful as a steroid- sparing agent. Children must be
monitored for side effects, including hypertension, nephrotoxicity, hirsutism, and gingival hyperplasia.
Unfortunately, most children who respond to cyclosporine therapy tend to relapse when the medication is
discontinued.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II blockers may be helpful as an adjunct therapy
to reduce proteinuria in steroid-resistant patients.
Complications.
Infection is the major complication of nephrotic syndrome. Children in relapse have increased susceptibility to
bacterial infections owing to urinary losses of immunoglobulins and properdin factor B, defective cell-mediated
immunity, immunosuppressive therapy, malnutrition, and edema/ascites acting as a potential “culture medium.”
Spontaneous bacterial peritonitis is the most frequent type of infection, although sepsis, pneumonia, cellulitis, and
urinary tract infections may also be seen. Although Streptococcus pneumoniae is the most common organism
causing peritonitis, gram-negative bacteria such as Escherichia coli may also be encountered. Because fever and
physical findings may be minimal in the presence of corticosteroid therapy, a high index of suspicion, prompt
evaluation (including cultures of blood and peritoneal fluid), and early initiation of antibiotic therapy are critical.
The role of prophylactic antibiotic therapy during relapse remains controversial.
All children with nephrotic syndrome should receive polyvalent pneumococcal vaccine (if not previously
immunized), ideally administered when the child is in remission and off of daily prednisone therapy. Children with
a negative varicella titer should be given varicella vaccine when in remission or on a low dose of alternate-day
steroids. Nonimmune nephrotic children in relapse exposed to varicella should receive varicella zoster immune
globulin (VZIG) within 72?hr of exposure. Influenza vaccine should be given on a yearly basis.
Children with nephrotic syndrome are also at increased risk for thromboembolic events. The incidence of this
complication in children is 2–5%, which represents a much lower risk than that of adults with nephrotic syndrome.
Both arterial and venous thromboses may be seen, including renal vein thrombosis, pulmonary embolus, sagittal
sinus thrombosis, and thrombosis of indwelling arterial and venous catheters. The risk of thrombosis is related to
increased prothrombotic factors (fibrinogen, thrombocytosis, hemoconcentration, relative immobilization) and
decreased fibrinolytic factors (urinary losses of antithrombin ill, proteins C and S). Prophylactic anticoagulation is
not recommended in children unless they have had a previous thromboembolic event. Overaggressive diuresis
should be avoided and use of indwelling catheters limited because these factors may increase the likelihood of
clotting complications.
Prognosis.

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The majority of children with steroid-responsive nephrotic syndrome have repeated relapses, which generally
decrease in frequency as the child grows older.
Although there is no proven way to predict an individual child's course, those children who respond to steroids
rapidly and those who have no relapses during the first 6 mo after diagnosis tend to follow an infrequently
relapsing course. It is important to indicate to the family that the child with steroid-responsive nephrotic syndrome
will not develop chronic renal failure, that the disease is generally not hereditary, and that the child (in the
absence of prolonged cyclophosphamide therapy) will remain fertile. To minimize the psychological effects of the
condition, the physician should emphasize that the child should be considered normal when in remission and may
have unrestricted diet and activity, without the need for urine testing for protein.
Children with steroid-resistant nephrotic syndrome, most often caused by focal segmental glomerulosclerosis,
generally have a much poorer prognosis (see Chapter 528 ). These children develop progressive renal insufficiency,
ultimately leading to end-stage renal failure requiring dialysis or renal transplantation. Recurrent nephrotic
syndrome develops in 30–50% of transplant recipients with focal segmental glomerulosclerosis. Plasmapheresis,
plasma protein absorption onto protein A–based columns, high-dose cyclosporine or tacrolimus, and angiotensin-
converting enzyme (ACE) inhibitors may reduce proteinuria in these patients.
Emedicine
Kidney biopsy should be performed prior to any immunosuppressive treatment, including steroids, in
patients younger than 1 year or older than 8 years and patients with recurrent gross hematuria, relevant family
history of kidney disease, symptoms of systemic disease, positive viral screens, and/or laboratory findings possibly
indicative of secondary nephrotic syndrome or INS other than minimal change nephrotic syndrome (MCNS), such
as sustained elevation in serum creatinine levels, low C3/C4 levels, positive ANA findings, and positive anti–double-
stranded DNA antibody findings. In these cases, histology guides treatment, and steroids may or may not be
indicated depending on the underlying etiology.

The treatment of steroid-sensitive INS, steroid-dependent and frequently-relapsing INS, steroid-resistant nephrotic
syndrome (SRNS) and FSGS are discussed in detail below. The treatment of mesangiocapillary glomerulonephritis
(MPGN), membranous nephropathy (MN), congenital nephrotic syndrome, and secondary nephrotic syndrome (eg,
lupus nephritis and vasculitis) are beyond the scope of this article.
 Corticosteroid (steroid) treatment (MCNS, INS that does not require initial biopsy)
o Induction therapy:
 Exclude active infection or other contraindications prior to steroid therapy.
 The original ISKDC protocol recommended oral prednisone or prednisolone at 60
mg/m2/d (2 mg/kg/d) daily for 4 weeks.
 Traditionally, the total daily dose was split into two doses. However, a single daily dose
of steroids has equal efficacy to split dosing and fewer side effects. 19
 Subsequent studies have shown that a longer, 6-week rather than 4-week, period of
initial steroid treatment reduces the subsequent rate of relapse. Thus, many centers
now prescribe the initial daily steroids for 6 weeks.20
o Maintenance therapy (following above induction therapy)
 Original guidelines recommended oral prednisone or prednisolone at 40 mg/m 2 (or 1.5
mg/kg) given as a single dose on alternate days for 4 weeks.
 Subsequent studies demonstrated that a longer alternate day maintenance period of 6
weeks resulted in a lower rate of relapse.20
 Thus, many centers now recommend daily induction steroid treatment for 6 weeks,
followed by alternate day maintenance therapy for another 6 weeks.

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  Following 6 weeks of alternate day treatment, steroids may be stopped or slowly
tapered over a variable length of time.
 Longer duration of alternate-day steroid treatment may further reduce the number of
children with subsequent relapses. An assessment of the Cochrane Database concluded
that, after the initial daily steroid induction phase, continuation of alternate day steroids
for 6 months could reduce the subsequent relapse rate by 33% compared with shorter
alternate-day treatment.21 No adverse effects were noted with the longer steroid
treatment, although the authors cautioned the adequate randomized controlled trials
comparing shorter versus long-term alternate day steroid treatment still needed to be
conducted.21
o Relapse therapy
 For infrequent relapses, steroids are resumed, although for a shorter duration than
treatment during initial presentation
 Prednisone 2 mg/kg/d(60 mg/m2/d) given as a single morning dose is administered until
proteinuria has resolved for at least 2 days.
 Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m 2)
given as a single dose on alternate days for 4 weeks. Steroids may then be stopped or
gradually tapered.
 Other therapy (all patients):
o Pneumococcal vaccine should be administered to all patients upon presentation, to reduce the
risk of bacterial infection and peritonitis.
o Diuretic therapy may be beneficial, particularly in children with symptomatic edema. The loop
diuretics (furosemide) given orally in usual amounts (approximately 1-2 mg/kg/d) are safe and
moderately effective; their administration, however, should be handled with care because
plasma volume contraction may already be present, and hypovolemic shock has been observed
with overly aggressive therapy. Metolazone may be beneficial in combination with furosemide
for resistant edema. Patients must be monitored carefully on this regimen. If the child is sent
home on diuretic therapy, the family must have clear guidelines about discontinuing therapy
when edema is no longer present and careful communication with the family should continue
o When a patient presents with anasarca and signs of intravascular volume depletion (such as high
hematocrit indicative of hemoconcentration), consideration should be given to administration of
25% albumin, although this is controversial. Rapid administration of albumin can result in
pulmonary edema. The authors' practice has been to administer 25% albumin at a dose of 1 g/kg
body weight given as a continuous infusion over 24 hours. Intravenous albumin may be
particularly useful in diuretic resistant edema, and in patients with significant ascites and/or
scrotal, penile or labial edema.
o Antihypertensive therapy should be given when hypertension is present and particularly if it
persists, but caution should be exercised. In some patients the hypertension will respond to
diuretics. ACE inhibitors or angiotensin II receptor blocker (ARB) agents may also contribute to
reducing proteinuria but should be used cautiously in the presence of acute kidney failure or
volume depletion because their use can worse kidney function in these settings. Adolescent
women must also be counseled regarding use of birth control with chronic ACE inhibitors or ARB
due to risk of birth defects, and pregnancy testing should be considered before starting these
agents. Calcium channel blockers and beta-blockers may also be used as first-line agents for
hypertension.

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 o Home monitoring of urine protein and fluid status is an important aspect of management. All
patients and parents should be trained to monitor first morning urine proteins at home with
urine dipstick. Weight should be checked every morning as well, and a home logbook should be
kept recording the patient’s daily weight, urine protein levels, and steroid dose if being treated.
Families and patients are instructed to call for any edema, weight gain, or urine protein findings
of 2+ or more for more than 2 days. Urine testing at home is also useful in monitoring response
(or nonresponse) to steroid treatment.
 Frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome (SDNS)
o Frequently relapsing nephrotic syndrome is defined as steroid-sensitive nephrotic syndrome
(SSNS) with 2 or more relapses within 6 months or more than 3 relapses within a 12-month
period.
o SDNS is defined a as SSNS with 2 or more consecutive relapses during tapering or within 14 days
of stopping steroids.
o For frequently relapsing nephrotic syndrome and SDNS, the clinical evidence is inadequate to
support a preferred method of treatment. Therefore, practitioners must rely on their clinical
experience and discuss the potential advantages and disadvantages of each treatment with
families and patients.22
o Alkylating agents (cyclophosphamide [CYP], chlorambucil, nitrogen mustard) offer the benefit of
possible sustained remission after a defined course of treatment, although with the risk of
infertility and other side effects (see Complications).
 Calcineurin-inhibitors (eg, cyclosporine [CSA], tacrolimus [TAC]) are useful steroid-
sparing agents, but prolonged courses of treatment are needed, nephrotic syndrome
tends to recur when treatment is stopped, and nephrotoxic injury may occur.
 An increased risk of seizures is noted with chlorambucil. 12 Additionally, a higher
incidence of infections and leukopenia may be seen with chlorambucil compared with
CYP.23 Because of these risks, and the need to give nitrogen mustard intravenously, the
authors have used cyclophosphamide as the preferred alkylating agent
 Cyclophosphamide (2–2.5 mg/kg daily) is given orally for 8-12 weeks.
 Steroids are usually overlapped with initiation of CYP then tapered.
 An influential study found that a 12 week course of cyclophosphamide was more
effective than an 8-week course in producing sustained remission of nephrotic
syndrome.24 However, a subsequent randomized trial did not reach this same
conclusion,25 and the optimal duration of cyclophosphamide treatment is still unclear at
this time.
 Patients must have weekly CBC counts to monitor for leukopenia.
 Patients must also maintain adequate hydration and take CYP in the morning (not at
bedtime) to limit the risk of hemorrhagic cystitis. Families must be counseled to report
gross hematuria, fever, or severe illness.
o Calcineurin-inhibitors
 CSA can be used in those children who fail to respond to, or subsequently relapse after,
treatment with CYP, or for children whose families object to use of CYP. Because CSA
can cause hirsutism and gingival hyperplasia, the authors' practice has been to
use TAC instead of CSA, although limited studies are available regarding the
effectiveness of TAC compared with CSA.
 Initial doses of CSA are started at 5–6 mg/kg daily divided every 12 hours, adjusted
for trough concentrations of 50–125 ng/mL. Low-dose steroids are continued for a

5
 variable length of time; as many as 40% of patients may need to remain on steroids
during CSA treatment to maintain remission.12
 Kidney function and drug levels must be carefully monitored due to the risk of CSA
induced nephrotoxicity.
 Trough levels correlate poorly with area-under-the-curve (AUC) pharmacokinetics and
may not represent true exposure to CSA. levels obtained 2 hours after administration
(C2) have better correlation with AUC.26
 TAC trough levels correspond better to AUC than CSA, allowing better determination of
dosing and exposure with TAC than with CSA.26
 TAC is started at a dose of 0.1 mg/kg daily divided every 12 hours and adjusted to keep
trough level about 5-10 ng/mL.27 Our practice is to use the lowest possible dose that
sustains remission and to aim for a trough level of around 5 ng/mL. As with CSA,
continuing low-dose steroids is often necessary to maintain remission, although some
patients may eventually be able to discontinue steroid treatment.
 With CSA and TAC, kidney function and drug levels should be carefully monitored.
Consideration should be given to kidney biopsy after prolonged treatment to monitor
for calcineurin-inhibitor induced nephrotoxicity and fibrosis.
 TAC (0.1-0.2 mg/kg/d) or CSA (5-6 mg/kg/d) have similar efficacy in inducing remission
in patients with idiopathic SRNS at 6 months and 1 year when combined with alternate-
day low-dose corticosteroids and enalapril.28 Relapse was significantly greater in those
who received CSA compared with TAC. TAC also decreased blood cholesterol levels to a
greater extent and resulted in less incidents of nephrotoxicity that necessitated
discontinuance than CSA. Cosmetic adverse effects (eg, hypertrichosis, gum
hypertrophy) were significantly more frequent in the CSA group (P <0.001). TAC therapy
is a promising alternative to CSA because of the lower relapse risk and lack of cosmetic
adverse effects.
o Levamisole: is an anthelmintic drug that has immune-modulating effects and can be effective in
reducing the relapse rate in frequently relapsing nephrotic syndrome. However, it is unavailable
in the United States. Side effects include leukopenia, hepatic dysfunction, agranulocytosis,
vasculitis, and encephalopathy. Levamisole is prescribed at a dose of 2.5 mg/kg given on
alternate days .12
o Mycophenolate mofetil (MMF): Although small studies have shown MMF to be effective in
reducing the number of relapses in frequently relapsing nephrotic syndrome and SDNS, adequate
randomized controlled trials still need to be performed. The authors have found MMF to be a
useful steroid-sparing agent in stable patients (without excessive edema, need for
hospitalizations and without other serious complications) whose families wish to avoid the
possible side effects of CYP, CSA, or TAC. However, response to MMF varies and is less reliable
than other treatments. MMF is started at a dose of 600 mg/m2 twice daily. CBC counts should be
monitored for bone-marrow suppression, and liver function test findings should occasionally be
monitored for hepatic toxicity.
 SRNS and FSGS
o Adequate randomized controlled trials have not yet been reported to give sufficient evidence to
guide treatment of SRNS.29
o A current, National Institutes of Health (NIH)-sponsored, multicenter, randomized clinical trial
has recently concluded enrollment and will compare CSA versus MMF for treatment of FSGS. 30

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 o The most frequently recommended treatment for FSGS and SRNS is CSA. Approximately 36% of
children with SRNS may achieve remission with CSA.29 CSA is dosed as above for FRNS and SDNS.
However, higher doses and trough levels may be required to achieve remission in SRNS and
FSGS.12 TAC may be effective as well, although studies are limited at this time. 30
o Most studies to date have shown no clear benefit to the use of alkylating agents in FSGS and
SRNS.6
o A controversial treatment involves high-dose, intravenous methylprednisolone tapered over 78
weeks, in combination with alternate day oral prednisone and with the addition of CYP or
chlorambucil if remission is not achieved in the first 10 weeks. The authors reported a 52%
remission rate in SRNS.31 However, subsequent studies using this protocol have not duplicated
the initial success. The risk of steroid toxicity and infection, as well as lack of sufficient evidence
for the effectiveness of this protocol, have dampened enthusiasm for this treatment.
o The use of an ACE inhibitor, such as enalapril, either alone or in combination with an ARB agents,
such as losartan, has been shown to reduce proteinuria in FSGS/SDNS and should be considered
in all patients, even in the absence of hypertension. Accordingly, ACE inhibitors and ARB agents
should be considered as preferred agents in patients with hypertension. ACE inhibitor and ARB
treatment may also have a renoprotective effect and slow progression of renal disease by
inhibiting pathways of fibrosis.30
Surgical Care
No routine surgical care is indicated for this condition. Occasionally, a patient with nephrotic syndrome either
presents with or develops clinical signs of an acute surgical abdomen, which is frequently due to peritonitis. The
diagnosis can usually be made clinically and confirmed by bacteriologic examination of the peritoneal fluid
aspirate. The organism most often responsible for the peritonitis is pneumococcus; however, enteric bacteria may
also cause peritonitis. Treatment is medical.