Invited Review

Nutrition in Clinical Practice

Volume 36 Number 2
Pediatric Nephrotic Syndrome: Pharmacologic and Nutrition April 2021 331–343
© 2021 American Society for
Management Parenteral and Enteral Nutrition
DOI: 10.1002/ncp.10622
wileyonlinelibrary.com

Kyle J. Hampson, PharmD, BCNSP, BCPPS, CNSC1,2 ; Morgan L. Gay, MS, RD,
CNSC3 ; and Molly E. Band, MHS, PA-C4

Abstract
Nephrotic syndrome is a common kidney disease during childhood that is characterized by alterations in glomerular filtration
and leads to protein, fluid, and nutrient loss in the urine. Most patients experience peripheral, gravity-dependent edema; however,
serious cases exhibit anasarca and ascites. Many long-term complications of the disease exist due to the underlying pathology and
the therapies used for treatment, including metabolic bone disease, micronutrient deficiencies, and hyperlipidemia. Pharmacologic
and nutrition interventions are key to appropriate management. Fluid and sodium restriction in combination with corticosteroids,
albumin, and diuretics are used to manage edema. Steroid-sparing therapies like alkylating agents and calcineurin inhibitors and
dietary modification to eliminate dairy and gluten may be warranted in patients with frequent relapses or steroid-refractory disease.
Nutrition clinicians should familiarize themselves with the nuances of treating this disease to optimize care for children with
nephrotic syndrome. (Nutr Clin Pract. 2021;36:331–343)

Keywords
electrolytes; kidney diseases; micronutrients; nephrotic syndrome; nutrition; pediatrics

Introduction consist of a network of slit diaphragm proteins.2 The struc-

Nephrotic syndrome (NS) is a disorder of the glomerular
capillary wall in the nephron that leads to massive protein
and fluid loss through the kidneys.1 It is a common child-
hood renal disorder that occurs in 2-7 per 100,000 children
worldwide and may present at any age during childhood
and adolescence.1 The disorder, caused by dysfunction in
the glomerular filtration barrier, can lead to massive fluid,
protein, and nutrient loss in the urine.1 Pharmacologic
and nutrition optimization are key to ensuring appropriate
growth and development in children while minimizing ad-
verse effects of therapies.
Pathophysiology and Disease Classification
The clinical effects of NS originate from cellular changes
in the glomerulus, which is responsible for filtering blood
in the kidney. Under normal conditions, filtration occurs
at the glomerular filtration barrier and removes waste
products and fluid while retaining erythrocytes and plasma
proteins, including albumin.1 The glomerular filtration bar-
rier comprises fenestrated epithelial cells, the glomerular
basement membrane, and glomerular epithelial cells, called
podocytes.2,3 Podocytes are footlike cells that wrap around
the glomerular capillaries and are connected by specialized
cell-cell junctions called slit diaphragms.1 Slit diaphragms
tural integrity of the podocytes and slit diaphragms play a
key role in filtration. In NS, damage or alteration occurs
to the podocyte or the slit diaphragm proteins, leading to
rearrangement of the podocyte actin cytoskeleton, change
in podocyte shape, and changes in signaling between the
slit diaphragm proteins and the podocytes that regulate
ultrafiltration.3,4 The aforementioned damage or alterations
From the 1 Division of Pharmacy Practice, Arnold and Marie
Schwartz College of Pharmacy and Health Sciences, Long Island
University, Brooklyn, New York, USA; the 2 Division of
Pharmacotherapy Services, The Brooklyn Hospital Center, Brooklyn,
New York, USA; the 3 Department of Pediatric Nephrology,
Connecticut Children’s, Hartford, Connecticut, USA; and the
4 Department of Pediatric Urology, Yale New Haven Hospital, New
Haven, Connecticut, USA.
Financial disclosure: None declared.
Conflicts of interest: None declared.
Received for publication July 27, 2020; accepted for publication
November 21, 2020.
This article originally appeared online on January 19, 2021.
Corresponding Author:
Kyle J. Hampson, PharmD, BCNSP, BCPPS, CNSC, Division of
Pharmacy Practice, Arnold and Marie Schwartz College of Pharmacy
and Health Sciences, Long Island University, 75 DeKalb Avenue,
L-35-8, Brooklyn, NY, USA.
Email: kyle.hampson@liu.edu
332 Nutrition in Clinical Practice 36(2)

Table 1. Potential Causes of Nephrotic Syndrome1,2,4,30 .

Classification Example

Genetic mutations Nephrin (NPHS1) (Finnish-type nephrotic syndrome), podocin

(NPHS2), podocyte actin cytoskeleton proteins CD2AP and INF2,
actin bundling protein actin-α4, WT-1 (Denys-Drash syndrome)
Bacterial infection Post-streptococcal glomerulonephritis, infectious endocarditis, syphilis
Viral infection Hepatitis B and C, human immunodeficiency virus, cytomegalovirus
Other infection Malaria, toxoplasmosis
Hematological diseases Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, leukemia, sickle cell
disease
Drugs NSAIDs, gold, penicillamine, ACE inhibitors, pamidronate,
interferon-alfa, mercury, heroin, lithium
Environmental antigens Poison ivy, bee sting, food allergies
Systemic diseases Systemic lupus erythematosus, diabetes mellitus

ACE, angiotensin-converting enzyme; NSAID, nonsteroidal anti-inflammatory drug.

can occur through a variety of mechanisms, which are tion or be part of a multisystem syndrome, like Pierson
discussed in the Idiopathic NS section below. When these syndrome.1,4
structural changes occur, the glomerular filtration barrier
loses its ability to retain plasma proteins, producing the Idiopathic NS
characteristic proteinuria associated with NS.3
Most cases of NS can be classified as idiopathic, which
Other factors may also play a role in the NS. The
usually presents after the first year of life.1 The most com-
presence of a circulating soluble mediator that increases
mon cause of idiopathic NS in children is minimal change
capillary membrane permeability at the cell wall and leads
disease (MCD), which accounts for roughly 80% of cases in
to albuminuria has been proposed.1,2 Although still uniden-
children older than 1 year.1,5 Although the cause of MCD
tified, it is postulated that the permeability factor is linked
is unknown, fusion and effacement of the podocyte foot
to immunoglobulin G and it may cross the placenta and
processes lead to a disruption in the glomerular basement
induce transient neonatal proteinuria.2 The immune system,
membrane, allowing for proteinuria and subsequent clinical
specifically T-lymphocyte activation through interleukin-
sequalae.5 It is postulated that mechanisms intrinsic to
2 and depressed cell-mediated immunity, may play a role
the podocyte, the presence of soluble circulating factors,
in the pathogenesis of NS.1 However, immune system ir-
and immune system dysregulation may contribute to the
regularities are not present in all patients with NS, and
pathogenesis of MCD.5 Focal segmental glomerulosclerosis
these effects have not been reproduced in animal studies.1 A
is more common in slightly older children (around 6 years
summary of the etiologies of NS are found in the following
old) and is characterized by segmental destruction of the
sections and in Table 1.
glomerular capillaries, which forms adhesions between the
sclerosed segments and the Bowman’s capsule.2,4 Less com-
mon causes of idiopathic NS include mesangial prolifer-
Congenital NS ative glomerulonephritis, membranoproliferative glomeru-
lonephritis, and membranous nephropathy.1,2 Regardless of
Although rare, congenital NS typically presents during
underlying etiology, the subsequent changes in the podocyte
the first 3 months of life and is largely due to genetic
shape and the rearrangement of the podocyte cytoskeleton
mutations in slit diaphragm proteins. The most common
caused by these abnormalities ultimately lead to the loss of
etiology is Finnish-type congenital NS, which involves a
serum protein through the glomerulus and subsequent signs
mutation in the gene encoding for the slit diaphragm
and symptoms of NS.4
protein nephrin (NPHS1).1,2 Mutations have also been
found in genes encoding for podocin (NPHS2), another
slit diaphragm protein; podocyte actin cytoskeleton pro-
Disease Classification and Definitions
teins CD2AP and INF2; actin bundling protein actin- The 2012 Kidney Disease: Improving Global Outcomes
α4; and WT-1, a transcription factor suppressor gene (KDIGO) guidelines define NS in children as hypoalbu-
that leads to Denys-Drash syndrome, among others.1,3,4 minemia, edema, and proteinuria (protein > 40 mg/m2 /h
NS presenting during this time frame may also be or protein-creatinine ratio > 2000 mg/g [>200 mg/mmol]
caused by congenital syphilis and cytomegalovirus infec- or protein > 300 mg/dL or 3+ on urine dipstick [in adults,
Hampson et al 333

Table 2. Terminology Used to Describe Nephrotic Syndrome in Children4,6 .

Term Definition

Complete remission uPCR < 20 mg/mmol or < 1+ on urine dipstick for 3 consecutive days
Steroid-sensitive nephrotic syndrome Attainment of complete remission within the initial 4 weeks of
corticosteroid therapy
Steroid-refractory nephrotic syndrome Failure to achieve complete remission after 8 weeks of corticosteroid
therapy
Relapse uPCR ≥ 200 mg/mmol or > 3+ protein on urine dipstick for 3
consecutive days
Frequent relapse >2 relapses within 6 months of initial relapse or ≥ 4 relapses in any
12-month period
Steroid dependence 2 consecutive relapses during corticosteroid therapy or within 14 days
of stopping therapy

uPCR, urinary protein:creatinine ratio.

Table 3. Recommendations for Sodium Restriction16 .
Age Sodium
0-6 months 120 mg/d or 1-2 mEq/kg
7-12 months 370 mg/d
1-3 years 1000 mg/d
4-8 years 1200 mg/d
9-18 years 1500 mg/d
proteinuria > 3.5 g per 24 hours]).4,6 Diagnostic tests may
include a renal biopsy, viral testing, antibody or compliment
levels, and genetic testing to determine the underlying cause
of NS.6
Because patients with NS have varying response to
treatment and because the disease is associated with re-
currence of symptoms, terminology has been developed to
characterize the type of disease a child has. Many of these
terms describe the disease in reference to the response to
the primary treatment, corticosteroids (discussed within the
pharmacologic therapy section below). These definitions
have been provided in Table 2.
Signs and Symptoms
Although diagnosis requires alterations in laboratory tests
like serum albumin level and urinalysis, patients can present
with a multitude of signs and symptoms. The 4 classic
symptoms of NS are the aforementioned proteinuria, hy-
poalbuminemia, edema, and hyperlipidemia.7 Upon ini-
tial diagnosis of NS, patients exhibit sudden onset of
peripheral, gravity-dependent edema, which results from
the increased glomerular permeability and hypoalbumine-
mia and corresponding reduction in oncotic pressure.7,8
Periorbital edema is more common in the morning and
becomes more noticeable in the arms and legs throughout
the day and can also include labial/scrotal edema.7 In severe
cases, anasarca may be present and lead to complications
like ascites, pulmonary edema, or pleural effusion.4 If this
occurs, the patient can develop respiratory distress, cool
extremities, and abdominal pain from hypoperfusion and
ileus.4 The intravascular volume depletion from loss of
oncotic pressure can also lead to oliguria and acute kidney
injury.4
There are 2 theories that describe the underlying eti-
ology of edema in NS: the underfill hypothesis and the
overfill hypothesis. The underfill hypothesis proposes that
nephrotic range proteinuria leads to hypoalbuminemia.2,4,7
This results in low plasma oncotic pressure, allowing fluid
to leak into the tissues, which results in intravascular
volume depletion, thus activating the renin-angiotensin-
aldosterone system and leading to further sodium and water
retention.2,4,7 Conversely, the overfill hypothesis proposes
that protein loss in the urine leads to a compensatory
retention of sodium that expands the intravascular volume
and, ultimately, overflows into peripheral tissues.4,7 The
epithelial sodium channel is the primary channel for sodium
resorption in the kidney and is found in the distal segment
of the nephron.4 In the overfill hypothesis, the epithelial
sodium channel is opened and allows for further influx of
sodium.4,7
Nutrition Requirements
Fluid, Calorie, and Protein Needs
Despite limited data, children with NS have unique nutrition
support needs. These needs may change based on the
etiology of the disease, classification of disease, and clinical
parameters (eg, growth patterns; a more detailed discussion
of growth is found below). A patient-specific approach to
nutrition support care is warranted.
When a pediatric patient with NS is experiencing edema,
moderate fluid restriction is recommended, especially if
the patient is hyponatremic.9,10 Sodium restriction is also
recommended during this time.9,10 (Recommendations for
334 Nutrition in Clinical Practice 36(2)

Table 4. Summary of Pharmacotherapy Dosing and Adverse Effects17,18 .

Medication Dosing Selected adverse effects

Prednisone/prednisolone See Table 5 Hypothalamic-pituitary axis suppression, weight

gain, loss of calcium, reduction in bone mineral
density, hyperglycemia, diabetes mellitus,
growth impairment/delay
Albumin 0.5-1 g/kg Anaphylaxis, hypersensitivity reactions, fever,
exacerbation of dehydration, intraventricular
hemorrhage (neonates)
Furosemide IV: dose of 0.5-2 mg/kg every 6-12 hours Black box warning: Profound diuresis and
(maximum: 6 mg/kg/d) electrolyte depletion if given in excessive
Oral: dose of 0.5-2 mg/kg every 6-24 amounts
hours (maximum dose: 6 mg/kg) Hypokalemia, hypomagnesemia, hypocalcemia
contraction alkalosis, nephrotoxicity,
ototoxicity
Amiloride 0.625 mg/kg/d divided every 12-24 hours Hyperkalemia
(maximum daily dose: 20 mg) (not
used clinically; dosing for edema
listed)
Cyclophosphamide 2 mg/kg/d for 8-12 weeks (maximum Bone marrow suppression, alopecia, hemorrhagic
cumulative dose: 168 mg/kg) cystitis, infection, gonadal
dysfunction/infertility, hyponatremia, SIAD,
hypocalcemia
Chlorambucil 0.1-0.2 mg/kg/d for 8 weeks (maximum Black box warnings: Bone marrow suppression
cumulative dose: 11.2 mg/kg) and carcinogen/teratogenicity/infertility seizures
Cyclosporine 4-5 mg/kg/d in 2 divided doses (starting Black box warnings: Serious infection, neoplasm,
dose) hypertension, and nephrotoxicity
Gingival hyperplasia, hirsutism, diabetes mellitus,
hyperkalemia, hypomagnesemia, neurotoxicity
Tacrolimus 0.1 mg/kg/d in 2 divided doses (starting Black box warnings: Serious infection and
dose) neoplasm
Hypertension, renal dysfunction, diabetes
mellitus, hyperkalemia, hypomagnesemia,
nephrotoxicity, neurotoxicity
Mycophenolate mofetil 1200 mg/m2 /d given in 2 divided doses Black box warnings: Serious infection,
for 12 months malignancy, embryo-fetal toxicity
Leukopenia, abdominal pain, diarrhea
Rituximab 375 mg/m2 per dose for up to 4 weekly Black box warnings: Infusion reactions,
doses mucocutaneous reactions, hepatitis B
reactivation, and progressive multifocal
leukoencephalopathy
Pulmonary toxicity, bone marrow suppression

IV, intravenous; SIAD, Syndrome of Inappropriate Anti-Diuresis.

sodium restriction can be found in Table 3.) Patients with
NS with edema have the same energy requirements as
healthy children of the same chronological age.9 A pro-
tein intake of 1-2 g/kg/d is adequate for most children
during this time.9 Another recommendation is to provide
between 130% and 140% of the recommended dietary
allowance of protein.10 In an attempt to improve serum
protein status, historical practice dictated a higher protein
provision (3-4 g/kg/d). However, this practice is not rec-
ommended owing to the concern that high-protein diets
may accelerate glomerulonephritis.9 Furthermore, a study
in rats that compared dietary protein intakes (8.5% vs
21% of total calories) did not demonstrate an effect on
serum albumin concentrations.11 Once edema has resolved,
maintenance fluid requirements can be provided. Children
should follow a healthy, age-appropriate diet to meet energy
requirements and the daily recommended intake for
protein.9 If catch-up growth is required, energy intake
may increase to 120%-140% of the recommended dietary
allowance.12 It is recommended to continue to limit sodium
and to also restrict saturated and trans fat, as these have
been linked to inflammation.10,13
Children with congenital NS have unique needs, which
are much greater than those of healthy children. Children
Hampson et al 335

Table 5. Corticosteroid Dosing From the KDIGO Guidelines6 .

Scenario Recommendation

Initial episode of -Oral prednisone or prednisolone 60 mg/m2 /d or 2 mg/kg/d as a single daily dose
steroid-sensitive nephrotic (maximum: 60 mg/d) for 4-6 weeks
syndrome -Then, alternate-day dosing of oral prednisone or prednisolone 40 mg/m2 /d or 1.5 mg/kg
as a single daily dose for 4-6 weeks (maximum: 40 mg/d on alternate days)
-Then, taper over 2-5 months
-Total duration: at least 12 weeks
Infrequent relapses of -Oral prednisone or prednisolone 60 mg/m2 /d or 2 mg/kg/d as a single daily dose
steroid-sensitive nephrotic (maximum: 60 mg/d) until child has been in complete remission for 3 days
syndrome -Then, alternate-day dosing of oral prednisone or prednisolone 40 mg/m2 /d or 1.5 mg/kg
as a single daily dose for at least 4 weeks (maximum: 40 mg/d on alternate days)
-Then, taper off
Frequent relapses or -Daily prednisone until the child has been in remission for at least 3 days
steroid-dependent -Then, alternate-day dosing of prednisone for at least 3 months, using the lowest dose to
steroid-sensitive nephrotic maintain remission without major adverse effects
syndrome -May use daily prednisone if alternate-day therapy is not effective
-May require doses for 3-6 months before tapering

KDIGO, Kidney Disease: Improving Global Outcomes.

with congenital NS may require as much as 130 kcal/kg
and, for protein, 2-4 g/kg.9 Fluid provision may need to be
restricted based on clinical status.9 Often, enteral nutrition
supplements will be required to meet energy needs within
the parameters of fluid restriction, if they can be met at all.9
Children with congenital NS may require a multivitamin to
meet the recommended dietary allowance of vitamins for
healthy children of the same age and may require additional
calcium and magnesium supplementation (doses based on
age and clinical condition: 200-1300 mg/d for calcium and
30-410 mg/d for magnesium).14–16
Pharmacologic Therapy
Pharmacologic therapy options for pediatric NS are dis-
cussed in detail in the following sections. When patients
are first diagnosed with the disease, flares are managed
with aggressivly with corticosteroids, albumin, and diuret-
ics, in addition to sodium and fluid restriction. Patients
that develop steroid-resistant disease or adverse effects to
corticosteroids may use steroid-sparing therapies and may
need to be managed more conservatively. Here, different
treatment modalities are discussed; a summary of dosing
and adverse effects can be found in Table 4.
Corticosteroids
Corticosteroids are the cornerstone of therapy for children
with NS, and fortunately, most children (80%-90%) with
NS will respond to steroid therapy.4 Multiple mechanisms
of action are thought to contribute to the efficacy of these
drugs. By modulating gene expression at the glucocorti-
coid receptor, corticosteroids increase anti-inflammatory
cytokines and decrease proinflammatory cytokines. They
can also suppress T-cell function.17 However, the most per-
tinent action of corticosteroids is their effect on podocytes.
Corticosteroids can stabilize or reverse changes to podocyte
shape and cytoskeleton rearrangement, which reduces loss
of protein through the urine.3 The KDIGO guidelines de-
lineate specific dosing recommendations for corticosteroids,
which are listed in Table 5.6 Special attention must be paid
toward the units used for dosing, and patient counseling
is key to appropriate medication administration, especially
for alternate-day regimens. It is preferred to administer
prednisone or prednisolone once daily in the morning, as
this mimics the daily endogenous release patterns of adrenal
corticosteroids.18
Despite the significant benefit that corticosteroids
have for patients with NS, significant adverse effects may
occur. Because the shortest duration of corticosteroid
treatment for NS is 4-6 weeks, hypothalamic-pituitary axis
suppression will be present in virtually all patients.18 Once
remission is achieved, corticosteroids should be weaned
conservatively, taking into account the duration of exposure
the child required. Because of hypothalamic-pituitary axis
suppression, if the child experiences trauma or infection or
needs surgery during treatment, a stress dose of corticos-
teroids may need to be given.18 Also pertinent for patients
requiring surgery is the impairment of wound healing that
may occur.17 Hyperglycemia and insulin resistance can be
seen with prolonged use and managed similarly to type 2
diabetes.19 Mild hyperglycemia may be treated with oral
agents, with insulin therapy reserved for more severe cases.19
Therapy should be reevaluated when corticosteroid doses
are changed or discontinued, as hyperglycemia typically
336
resolves within 48 hours after changes in corticosteroid
therapy.19
Patients receiving corticosteroids can also experience
fluid retention and weight gain (both from fluid and from
an increase in appetite).9 Controlling excess weight gain
is an important component in providing nutrition care
to patients with appetite stimulation.9 Data regarding di-
etary management of corticosteroid-induced weight gain
in children are sparse. A recent meta-analysis identified
only 2 studies regarding obesity prevention in pediatric
patients receiving corticosteroids during treatment of acute
lymphoblastic leukemia, but they found that diet combined
with exercise leads to less of an increase in body mass index
(BMI) z-scores.20 This underscores the importance of diet
education to encourage an overall healthy diet and low-
calorie alternatives for snacks.9 If patients experience weight
gain, psychosocial support regarding perception of body
image may be beneficial, especially in adolescents. 9
Corticosteroids are also known to reduce calcium resorp-
tion by increasing renal losses in the kidney and reducing in-
testinal absorption.19,21 The immediate risk is a loss of bone
mineral density (BMD), leading to metabolic bone disease
(MBD) (osteopenia, osteoporosis, and osteonecrosis).19
This mainly affects trabecular bone in the axial skeleton
(spine, hips, and ribs) and may lead to fractures.19 As little as
5 mg of prednisolone per day decreases BMD and increases
the risk of fracture.9 It is estimated that 30%-50% of patients
receiving long-term corticosteroids develop steroid-induced
osteoporosis.22 A discussion of MBD in patients with NS
is found within the nutrition and metabolic complications
section below.
New research using metabolomics and proteomics has
identified biomarkers that can help predict patient response
to corticosteroid therapy.23,24 Although more research is
needed to validate these findings, these data may allow
targeted pharmacologic and nutrition interventions for pa-
tients with NS.
Albumin
Albumin and diuretics (described here and in the diuretics
section) are given concomitantly for management of edema.
Albumin is given to increase oncotic pressure within the
vasculature, therefore increasing the osmotic gradient and
creating a shift of water from the peripheral tissues and
interstitium back into the intravascular compartment.18,25
Despite the hypoalbuminemia that is characteristic of NS,
albumin is not given to replace the protein that is lost
in the urine or to replete a low serum albumin level.
Albumin is dosed as 0.5-1 g/kg over 30-60 minutes and is
given sequentially before diuretics.18 It can be repeated as
frequently as every 6 hours based on patient response (ie,
resolution or significant reduction in edema).18 The more
concentrated 25% albumin product is used in the treatment
Nutrition in Clinical Practice 36(2)
of NS, as this allows less volume and sodium to be given to
these already fluid- and sodium-restricted patients.17,18
The adverse effects of intravenous albumin provision can
be serious, including anaphylactic/hypersensitivity reactions
and fever.17 Given the excretion of fluid that rapidly shifts
back into the intravascular compartment because of the
changes in oncotic pressure, albumin use may exacerbate
existing dehydration, if present. Another serious adverse
effect that can be seen in neonates is intraventricular
hemorrhage.26 There are also many complications to the
administration of albumin. Because it interacts and binds
with many medications and nutrients (eg, zinc), albumin
provision usually requires a dedicated central line.27 No-
tably, albumin destabilizes when given concurrently with
intravenous lipid emulsions.28
Diuretics
The overfill and underfill hypothesis of edema may seem
contrary to one another; however, in all likelihood, there is
some overlap between these theories in patients.4 Regardless
of the etiology, the goals of therapy in an edematous state
are to reduce edema by drawing the fluid back into the
vasculature with albumin and then excreting the excess fluid
with diuretics.4
Loop diuretics exert their action in the ascending loop
of Henle, which is responsible for resorption of about
15%-25% of sodium.29 Loop diuretics exert their action
by blocking the Na+ /K+ /2Cl− cotransporter, which in-
hibits the reabsorption of sodium and chloride into the
bloodstream.29 Water then follows this sodium, and the net
effect is increased excretion of water and electrolytes in the
urine.4
The most common loop diuretic used is furosemide,
which is usually given intravenously as 0.5-2 mg/kg every
6-12 hours (maximum dose: 6 mg/kg/d) for acute edema.17
Starting doses are typically around 1 mg/kg but can be
titrated upward.18 Increasing the dose helps to increase
intratubular concentration of furosemide, as furosemide is
usually bound to albumin in the tubular lumen in patients
experiencing proteinuria.30 Some patients may require pe-
riodic dosing of furosemide, which can be given orally.
Oral furosemide is dosed 0.5-2 mg/kg every 6-24 hours
(maximum dose: 6 mg/kg/d).17 An equivalent dose of oral
furosemide is twice the intravenous dose because of low oral
bioavailability.17 Additionally, if the bowel is edematous,
there can be a further reduction in oral bioavailability.31
Furosemide can cause significant adverse effects, and
judicious patient selection is key to safe use. Furosemide has
a black box warning for profound diuresis and electrolyte
depletion if given in excessive amounts.17 Electrolyte distur-
bances, like hypokalemia, hypomagnesemia, and hypocal-
cemia, may also occur. Of note, hypomagnesemia may make
it harder to replete potassium. If both are low, the mag-
Hampson et al
nesium should be given prior to repleting the potassium.21
Furosemide is also known to cause a contraction alkalosis.
Ototoxicity is largely a theoretical risk but may be seen with
chronic, high doses.17
Amiloride is a potassium sparing diuretic that works
by inhibiting the sodium-potassium ion exchange in the
collecting duct.29 This leads to decreased sodium resorption
and, in turn, increased excretion of sodium and water.29
Amiloride also blocks the activation of the epithelial
sodium channel.4 The epithelial sodium channel is activated
in the overfill hypothesis, leading to sodium and water
retention.4 By preventing this, amiloride will facilitate elim-
ination of sodium and water, reducing edema. Amiloride in
combination with furosemide produces greater diuresis than
furosemide alone in children with NS.4 The use of amiloride
as monotherapy in pediatric NS is theoretical and has never
been studied.4
Steroid-Sparing Therapies
As previously discussed, corticosteroid use comes with
many adverse effects and metabolic complications. The
KDIGO guidelines recommend steroid-sparing therapies
for patients that exhibit adverse effects to corticosteroids.6
Alkylating Agents
The KDIGO guidelines specifically recommend the use of
alkylating agents cyclophosphamide and chlorambucil as
steroid-sparing therapies for patients with frequently relaps-
ing and steroid-dependent disease.6 Use of these agents can
reduce the risk of relapse without corticosteroids and can
extend remission by >1 year.8 These medications work by
inhibiting DNA synthesis by alkylation and cross-linking
strands of DNA, leading to apoptosis of immunological
cells that contribute to glomerular membrane permeability.8
Cyclophosphamide is a prodrug that is converted to the
active form in the liver and is the more commonly used
alkylating agent. The benefit from cyclophosphamide is re-
lated to the length of treatment, with the optimal treatment
being 8-12 weeks.6 This benefit must be balanced with some
potentially serious side effects, most notably hemorrhagic
cystitis.17 Before therapy can be initiated, the child must
have an appropriate urine output (>1 mL/kg/h) and must be
able to meet hydration needs orally. Cyclophosphamide can
also cause hyponatremia, syndrome of inappropriate an-
tidiuresis, hypocalcemia, and bone marrow suppression.17
An important drug-nutrient interaction exists with the use
of cyclophosphamide and grapefruit. Cyclophosphamide is
converted to its active form by cytochrome 3A4, which is
inhibited by grapefruit. This can lead to an impairment in
the conversion of cyclophosphamide to its active form.32
It is recommended to avoiding grapefruit and grapefruit
products when taking cyclophosphamide.32 This includes
not only grapefruit, grapefruit juice, and concentrate but
337
also products that contain grapefruit juice, like Fresca and
gummy bears.
Chlorambucil is used less frequently because it is as-
sociated with more adverse effects, but it can be used as
an alternative to cyclophosphamide.18 These adverse effects
include black box warnings for bone marrow suppression
and teratogenicity.17 It also carries a risk of seizures.17,18
Both of the alkylating agents should have their use limited to
1 course, because of the risk of gonadal toxicity. Although
this may develop in both genders, the most common type of
gonadal toxicity is azoospermia in males.6
Calcineurin Inhibitors
Another class of medications that can be used as steroid-
sparing therapies in pediatric NS are the calcineurin in-
hibitors cyclosporine and tacrolimus. Cyclosporine causes
renal artery vasoconstriction and reduces glomerular per-
meability, stabilizing the podocyte cytoskeleton and causing
less protein to pass into the urine.8,18 Initial doses are be-
tween 4 and 5 mg/kg/d divided twice daily.6 Because of ad-
verse effects, the lowest effective dose of cyclosporine should
be used, but doses can be titrated to a goal trough level
of 60 and 100 ng/mL.4 These adverse effects include black
box warnings for serious infection, neoplasm, hypertension,
and nephrotoxicity.17 Notably, metabolic adverse effects can
include diabetes mellitus, hyperkalemia, and hypomagne-
semia. Other adverse effects include gingival hyperplasia,
hirsutism, and neurotoxicity. Of note, cyclosporine products
have variable bioavailability and cannot be substituted for
one another.18
Tacrolimus is another calcineurin inhibitor that is
thought to reduce vascular permeability factor, which con-
tributes to the massive proteinuria seen in patients with
MCD.18 Initial doses start at 0.05-0.1 mg/kg/d divided
twice daily and are titrated to a goal trough level of 5-
10 ng/mL.6,18 Tacrolimus also has many significant adverse
effects, including black box warnings for serious infection
and neoplasm.17 Tacrolimus is more likely to cause diabetes
than cyclosporine and is also associated with hyperkalemia,
hypomagnesemia, neurotoxicity, and renal dysfunction.4,18
Many patients will require magnesium supplementation and
dietary modification to limit potassium intake.
Many children with NS present with hypertension. A
known adverse effect of calcineurin inhibitors is their ability
to cause hypertension, which may worsen this preexisting
hypertension.18 Medications like angiotensin-converting en-
zyme inhibitors or angiotensin receptor blockers can be
used. These medications may also have some antiproteinuric
effects, although the data are much stronger supporting this
effect in adults than in children.18
Because of the risk of nephrotoxicity, prolonged use
of calcineurin inhibitors is controversial, and therapy is
usually limited to 2 years.6 Similar to the alkylating agents,
338
both calcineurin inhibitors should also not be used with
grapefruit products, as grapefruit can cause an increase the
oral bioavailability of the drugs.32
Mycophenolate
Mycophenolate is another agent that may be used as
a steroid-sparing treatment for NS. Mycophenolate is a
purine synthetase inhibitor and is useful in NS because
it inhibits proliferation of mesangial cells, a type of cell
in the glomerulus that is involved in removing protein
from the basement membrane of the renal corpuscle.18 My-
cophenolate is dosed at 1200 mg/m2 /d (about 30 mg/kg/d)
and is given in 2 divided doses.6,17,18 Mycophenolate does
have black box warnings for serious infection, malignancy,
and embryo-fetal toxicity and can also cause leukopenia,
abdominal pain, and diarrhea.8,17,18 In general, mycopheno-
late is considered to have fewer side effects than alkylating
agents and calcineurin inhibitors but also may be less
effective.18 It is most useful in patients with renal toxicity
from other therapies or progressive renal toxicity.18
Rituximab
Rituximab is a B cell-depleting chimeric antibody that has
activity against the CD20 surface antigen on B cells.18
Although its role in therapy is still being defined, ritux-
imab can be used in both steroid-sensitive and steroid-
resistant disease and can be used for children with steroid-
dependent NS (SDNS) who have frequent relapses despite
optimal combinations of prednisone- and corticosteroid-
sparing agents or have serious adverse effects to therapy.4,6
Rituximab is dosed at 375 mg/m2 and is given as a single
dose.6,18 Rituximab can have serious adverse effects, includ-
ing serious infusion-related reactions, which may be mild
(fever or rash) or severe (hypotension and bronchospasm).6
Rituximab-associated lung injury (RALI) is a serious pul-
monary toxicity. RALI is typically transient and reversible
but may lead to potentially fatal complications, including
pulmonary fibrosis and interstitial pneumonitis.18 RALI
can present between 1 and 3 months after initiation of
rituximab. It is recommended that patients obtain a chest
x-ray prior to initiating rituximab and periodically during
therapy to allow for comparison and early identification of
RALI.18
Nutrition and Metabolic Complications in
Pediatric NS
Growth
Given the chronic, relapsing nature of NS that leads to re-
peated protein loss and prolonged periods of drug exposure,
NS has significant implications for growth and development
in children with this disease. A recent retrospective study of
Nutrition in Clinical Practice 36(2)
patients with congenital NS showed reductions in weight
standard deviation score (SDS) and small reductions in
height SDS after 6 months of dialysis.33 The authors con-
cluded that although unsatisfactory, this was consistent with
children receiving dialysis for other primary renal diseases.33
In addition to this study,33 use of specific medications
in pediatric NS have been shown to affect growth. Sev-
eral studies have assessed the effect of steroid therapy on
various markers of growth in steroid-sensitive and steroid-
refractory disease. Emma and colleagues analyzed growth
data of 56 patients with steroid-sensitive (n = 42) and
frequently relapsing (n = 14) disease and found that pred-
nisone use was associated with a negative height SDS,
regardless of treatment modality (including dose, duration
of induction, and duration of total therapy for relapse).34
This study also found that both prepubertal and pubertal
height SDS was negatively impacted regardless of gender,
but boys had a delay in their peak pubertal growth spurt
and a delay in reaching their final height. Additionally,
children who experienced onset of NS before 3.5 years of
age had significantly worse linear growth before puberty.34
Another retrospective analysis of 85 patients with steroid
responsive NS found that both duration of prednisone
use and total prednisone dose significantly affected height
percentile loss but that age of first consultation did not.35
Based on their data of mostly male patients, the authors
postulate that control of NS flares, discontinuation of
therapies prior to adolescence, and catch-up growth after
discontinuation of steroids and the pubertal growth spurt
are related to increases in height.35 Furthermore, they state
that prolonged duration of steroid therapy and use of higher
total doses of prednisone likely contributed to delay of the
pubertal growth spurt.35 More recent data have provided
evidence confirming the negative effects of corticosteroids
on growth. In a retrospective study of 30 patients with
steroid-sensitive NS (SSNS; n = 15), SDNS (n = 8), or
steroid-resistant NS (SRNS; n = 7), change in height z-score
was found to be negatively associated with the cumulative
dose of corticosteroids.36 This effect was found to be more
prominent in patients with SDNS or SRNS. Furthermore,
height z-scores were significantly lower in patients receiving
high-dose steroids (>0.4 mg/kg/d) as compared with those
receiving medium-dose (0.2-0.4 mg/kg/d) or low-dose (<0.2
mg/kg/d) steroids.36
The effects of steroid-sparing therapies on growth have
also been assessed. Mohan and Kanitkar documented a
correlation between increasing cumulative steroid dose and
a reduction in height in 35 patients with SSNS that received
steroids alone or steroids with a steroid-sparing agent
(eg, cyclophosphamide).37 The authors proposed that the
steroid-sparing therapies be used for patients who show
signs of decreased growth velocity.37 One longitudinal study
followed 64 male patients with SDNS that were exposed to
steroids and cyclosporine A for a median of 10 years. This
Hampson et al
study found that median height was stable throughout the
first 5 years but that reductions in height SDS progressed
over time, becoming statistically significant at 9 years.38
Although most patients in this study did not reach the height
of their genetic potential, adult height was normal for all but
2 patients. Interestingly, no correlation between cumulative
steroid dose and change in height was found.38 Additionally,
a study of 41 patients with idiopathic NS (both SSNS and
SRNS) receiving rituximab found that in both the SSNS and
SRNS groups, the height z-score improved after rituximab
treatment, but a reduction in BMI was seen.39 Although
these studies provide interesting insight, the retrospective
nature and limited sample size underscore the need for
stronger data to guide therapy and optimize growth in
children with NS.
Metabolic Bone Disease
MBD is of key concern in children with NS, and the
development of this complication is multifactorial. NS can
lead to several biochemical derangements from the loss
of plasma proteins and minerals in the urine, including
the loss of vitamin D binding protein, which can lead to
low vitamin D levels.22,40 Demonstrating this, one study
showed that 13 of 14 patients had vitamin D deficiency at
the time of NS diagnosis (only 5 children received prior
vitamin D supplementation).41 A larger, prospective study
of 61 patients with pediatric NS from the Midwest Pediatric
Nephrology Consortium found that all patients had low 25-
OH vitamin D levels pf <20 ng/dL at study enrollment, with
a median 25-OH vitamin D level of 9 ng/dL.42 At follow-up
(2.1-3.4 months later), 53% of patients still had low 25-OH
vitamin D levels of <20 ng/dL, and 84% had low 25-OH
vitamin D levels of <30 ng/dL.42
Corticosteroid use is also contributory to MBD, as
these drugs reduce intestinal absorption of calcium and
reduce the resorption of calcium in the renal tubule,
leading to calcium loss in the urine.21 Lower total
and ionized calcium levels have been documented with
both SSNS and steroid-refractory NS and was associ-
ated with risk of osteopenia and osteoporosis.43 Hypocal-
cemia may be transient and normalize in disease remis-
sion, but children with repeated relapses who require
repeated courses of corticosteroids may be at greater
risk of the development of MBD.22 Ultimately, these
deficiencies in calcium and vitamin D may lead to osteope-
nia and osteoporosis.43 Corticosteroids are known to inhibit
osteoblast development and activity, increase the osteoclast
life span, and suppress growth hormone and release of
parathyroid hormone.40 The net effect of corticosteroids
on the bone is decreased bone formation and overall bone
strength.40
Multiple studies have evaluated BMD in children with
NS. A cross-sectional study found that children with fre-
339
quently relapsing or steroid-refractory disease had lower
BMD z-scores in comparison with children who experienced
infrequent relapses (−2.70 ± 1.28 vs 1.30 ± 1.54; P =
.0317).44 Furthermore, an epidemiologic study of 100 chil-
dren with idiopathic NS and normal renal function found
that 61% of children had osteopenia and 22% of children
had osteoporosis.22 Multivariate regression identified older
age at onset of NS, lower total calcium intake, and greater
cumulative steroid dose as predictive of a low BMD z-
score.22 When these children were provided with calcium
and vitamin D supplementation (fixed doses of 500 mg
calcium carbonate [200 mg elemental calcium] and 200 IU
of vitamin D3 ) and followed longitudinally for 6 months,
61% of patients showed improved spinal BMD and 31%
showed a stable spinal BMD.45 The mean spinal BMD
values were improved for the entire group from baseline
with a corresponding improvement in mean baseline per-
centage z-score.45 Calcium and vitamin D supplementation,
increased dietary calcium intake, and lower steroid dose
were predictive of improved BMD z-score.45 Importantly,
these studies excluded patients with edema and patients
with evidence of malnutrition. It is likely that poor baseline
nutrition status will augment these abnormalities.
In managing patients with NS and vitamin D deficiency,
calcium and vitamin D supplementation is key. Patients
should receive diet counseling to improve the calcium and
vitamin D intake from foods. If dietary intervention does
not sufficiently improve calcium and vitamin D levels at
follow-up, supplementation is warranted. Calcium should
be supplemented to meet the daily recommended intake, and
vitamin D should be supplemented in escalating doses.16
Although literature has reported providing between 200 and
1000 IU of cholecalciferol daily from 2 months to 1 year,
a recent randomized, open-label study suggests that pro-
viding 60,000 IU cholecalciferol once a week and calcium
(250 mg twice daily if child is <20 kg and 500 mg twice
daily if child is >20 kg) improved 25-OH vitamin D levels
and reduced parathyroid hormone levels.14 In addition to
vitamin D levels, serum phosphorus, ionized calcium, ion-
ized parathyroid hormone, and alkaline phosphatase should
be monitored periodically to aid in patient assessment.14,46
Although, traditionally, total 25-OH vitamin D has been
used in assessment, recent literature supports the use of free
25-OH vitamin D levels in proteinuric renal diseases, like
NS.46 In line with the guidelines for nutritional rickets, this
study described deficiency as a 25-OH vitamin D level of
<12 ng/mL and sufficiency as a 25-OH vitamin D level of
>20 ng/mL.46
Micronutrient Deficiencies and Anemia
In addition to the loss of albumin and vitamin D binding
protein in the urine, patients with NS may also experi-
ence urinary loss of transferrin, erythropoietin, ceruloplas-
340
min, transcobalamin, iron, and trace elements.47 The exact
mechanism of these losses is still unclear; however, these
deficiencies are more common in patients with therapy-
resistant disease and may lead to the development of an
anemia that persists despite adequate supplementation with
iron and erythropoietin.
Urinary loss of transferrin in pediatric NS is well
documented.47 Iron is bound to this transferrin, and the
alkalotic environment of the urine allows iron to stay bound
to transferrin, allowing both to be lost through excretion.47
One study that compared 13 children with NS with histori-
cal controls found that both transferrin and iron deficiency
will occur during relapse of NS.48 Although this iron loss
alone may lead to anemia, low erythropoietin levels have
also been reported in children with NS. Correction of iron
deficiency anemia in these patients requires iron replace-
ment therapy, and patients with low erythropoietin levels
should also receive erythropoietin.47 These therapies should
correct iron and erythropoietin levels; however, transferrin
will not correct until the proteinuria is resolved.47
If patients have laboratory values consistent with anemia
from other micronutrient deficiencies or do not respond
to iron and erythropoietin therapy, deficiencies in other
micronutrients like copper, zinc, and vitamin B12 should
be considered.47 Hyporesponsiveness to erythropoietin may
be caused from iron, zinc, or copper deficiency.49 Ceru-
loplasmin, the carrier protein for copper, is lost in the
urine, which may induce copper deficiency.47 The activity
of copper and zinc superoxide dismutase is reduced in
copper deficient red blood cells, which shortens the life
span of those cells.49 Urinary losses of zinc have also
been documented in patients with NS.50 A recent meta-
analysis and systematic review of 6 studies evaluated the
use of zinc in pediatric patients with SDNS or Frequently
Relapsing Nephrotic Syndrome (FRNS) and suggests that
zinc therapy added to standard therapy may reduce the
number of relapses at 6 months and 12 months and may
help induce remission.51 Although the studies included were
found to be of "very low quality," this presents an exciting
area for future research on the effects of this micronutrient
in pediatric NS.51 Finally, urinary losses of vitamin B12
and transcobalamin in pediatric NS have been described,
but the impact of this on the development of anemia is
unknown.47
Dyslipidemia
Dyslipidemia can be observed during active NS owing to
compensatory protein and lipoprotein synthesis in response
to protein loss in the urine.1 Elevations in total cholesterol
(TC), low-density lipoprotein cholesterol (LDL-C), triglyc-
erides (TGs), phospholipids, and apolipoprotein B (apo
B)-containing lipoproteins (eg, very low-density lipopro-
tein cholesterol [VLDL-C], intermediate-density lipopro-
Nutrition in Clinical Practice 36(2)
tein, and lipoprotein[a]) may be present.52,53 Additionally,
hyperlipidemia and hypertriglyceridemia have both been
reported with corticosteroid use. This complication of NS
is due to increased hepatic lipoprotein synthesis in the
liver, reduced transport of cholesterol in the bloodstream
due to hypoalbuminemia, decreased activity of lipoprotein
lipase, and acquired lecithin cholesteryl acetyltransferase
deficiency through urinary losses.4 These metabolic abnor-
malities often resolve upon the resolution of proteinuria
and the discontinuation of corticosteroids.19 However, ad-
ditional research has shown that this may not be true for
all children with NS. A study of 25 children with NS found
that hyperlipidemia was correlated to disease relapse and
that hyperlipidemic profiles were present in nearly half of
children in the study at remission.54
The long-term effects of dyslipidemia in pediatric NS on
long-term cardiovascular events is unclear, and to date, there
are no data to support a link between dyslipidemia in these
patients and myocardial infarction, stroke, or mortality
in adulthood.55 However, dyslipidemia may contribute to
atherosclerosis and fatty streaks on the aorta and coro-
nary vessels that may evolve into plaques. Development of
atherosclerosis in children with NS is likely multifactorial,
as these children experience other risk factors for atheroscle-
rosis, like hypoalbuminemia, hypertension, hypercoagulable
state, and obesity.55 Because of these atherogenic risk fac-
tors, it is likely that the atherosclerotic process is accelerated
in pediatric NS.56
Management of dyslipidemia in pediatric NS involves
interventions that are used to treat dyslipidemia in children
that do not have NS. This begins with dietary optimiza-
tion. Overall, dietary strategies are focused on a balanced,
healthy diet with reduced saturated fat intake and increased
monounsaturated, polyunsaturated, and ω-3 fatty acids.9
In children older than 2 years, the National Heart, Lung,
and Blood Institute recommends use of the Cardiovascular
Health Integrated Lifestyle Diet (CHILD-1) for initial man-
agement of dyslipidemia.55 This diet recommends adequate
calories to support normal growth and development but
limits saturated fat intake to <10% of total calorie provision
and limits cholesterol consumption to <300 mg/d.55 It
is recommended that children with hyperlipidemia follow
CHILD-2, a diet plan that limits trans fats, restricts dietary
fat to <7% of total calories, and limits cholesterol intake
to <200 mg/d.55 Children under 2 years old should not
restrict fat intake, and breastfeeding is permitted when
recommended.55 Exercise and weight loss in overweight
patients can help augment the effects of these dietary
changes.
Because of a lack of data in children with NS, the use of
pharmacologic agents to treat dyslipidemia in pediatric NS
remains controversial but may be warranted in some high-
risk patients.54
Hampson et al
The most common agents used to manage dyslipidemia
in these children are 3-hydroxy-3-methylglutaryl coenzyme
A reductase inhibitors, commonly known as “statins.”
These medications inhibit cholesterol synthesis and increase
LDL-C receptors, leading to improved LDL-C and apo B-
containing lipoproteins.55 Administration is known to be
safe in children, but few studies have investigated these
medications specifically in pediatric NS patients.
Coleman and Watson first investigated use of simvas-
tatin with dietary modification in 7 children with SRNS.
Patients initially underwent dietary modification with an
individualized diet that met dietary recommendations for
energy, vitamins, and minerals for age, followed by initiation
of 5 mg of simvastatin, with doses titrating up based on
response and tolerance.57 Children experienced an 8.3%
reduction in TC with dietary modification alone and a 30%
reduction in TC after 2 months of dietary modification
with simvastatin.57 The total decrease in cholesterol was
41% after 6 months of this treatment.57 A reduction in
TGs of 13.8% was seen with dietary modification alone.57
After the addition of simvastatin to dietary modification,
the reduction in TGs was 36% after 2 months and 44% after
6 months of therapy.57 Another study assessed the use of
lovastatin or simvastatin in 12 patients with NS refractory
to steroids and other treatments. No dietary modification
was prescribed, and patients received a maximum of 20 mg
of lovastatin per day or 40 mg of simvastatin per day.58
Patients receiving statin therapy saw a reduction in TC
of 32% at 2 months and 40% in 6 months (which was
sustained 12 months after initiation).58 Additionally, TGs
were significantly lower by 4 months of therapy.58 More
recently, a randomized, placebo-controlled trial including
30 children with steroid-refractory NS demonstrated no
difference in LDL-C levels with 10 mg of atorvastatin daily
vs placebo after 12 months of therapy.59 Although this study
did find a significant reduction in the secondary end point of
apo B levels, little can be drawn from this information given
the small sample size and large number of patients that did
not complete the trial.59
One study of gemfibrozil, a fibrate therapy, has been
completed in pediatric patients with NS. Fibrates work
on peroxisome proliferator-activated receptor-α (PPAR)
receptors, leading to reductions in VLDL-C and TG.55 This
small randomized study provided gemfibrozil to 7 patients
and found a 34% reduction in TC, a 30% reduction in LDL-
C, and a 54% reduction in TG.60 Patients who received
gemfibrozil had no adverse effects, demonstrating safety and
a potential role for this therapy.60
More robust data are needed to support the routine
use of these therapies in children with NS. The KDIGO
guidelines do not recommend starting statin therapy for all
children or adolescents with chronic kidney disease (CKD),
because of the lack of safety data and data supporting
clinical benefit.56 The guidelines recommend that all chil-
341
dren with CKD should employ therapeutic lifestyle changes
but only recommend statin therapy for children with severe
LDL-C elevation based on clinical circumstances.56 For
children and adolescents with elevated TGs, the KDIGO
guidelines recommend lifestyle changes for patients with a
TG concentration of >500 mg/dL and do not recommend
specific TG-lowering agents, because of a lack of long-term
safety data.56
In adults, the use of bile acid sequestrants, nicotinic acid,
and ezetimibe is been well documented in patients with
NS; however, data do not exist describing the use of these
agents in children with NS. More data are also needed be-
fore emerging therapies, like lipid apheresis and proprotein
convertase subtilisin/kexin type 9 (PCSK9) inhibitors, can
be routinely utilized for pediatric NS.55
Food Sensitivities and Dietary Elimination
Interventions
A paucity of data exists regarding the Western diet and
dietary intervention for the management of NS. However,
case reports and case series of dietary intervention have
detailed success in control of refractory NS with reduc-
tion in medication use.61–63 The first report of dietary
sensitivity involved 6 children with steroid-responsive NS
with frequent relapses that required repeated courses of
corticosteroids.61 Patients were placed on an elemental tube-
feeding formula until urinary protein elimination was <500
mg in 24 hours.61 Once this was achieved, patients were
given a cow’s milk challenge, in which all patients saw
the rapid return of edema and proteinuria and return to
remission once the elemental diet was restarted.61 Intrader-
mal skin testing showed that the patients had cow’s-milk
protein sensitivity.61 An additional investigation showed
that in 26 patients for whom steroid therapy had failed,
6 patients achieved complete remission after employing
food avoidance, and 5 of these patients were able to stop
corticosteroid therapy.62 Foods that precipitated sensitivi-
ties included milk, chicken, egg white, gluten, pork, wheat
flour, and beef.62 A case series of 8 patients with SSNS
with a steroid-dependent or frequently relapsing pattern or
with SRNS treated with a gluten-free diet showed that all
patients experienced a reduction in the relapse rate when
compared with the prior year.63 All patients were also
able to lower the dose or discontinue steroids and other
immunosuppressive medications.63 Although data in this
area are limited, gluten-free diets are known to modulate
the gut microbiota and reduce bacteria-induced cytokine
production, reducing the release of inflammatory mediators
that are responsible for increasing glomerular permeability
to protein.63,64 Additionally, implementation of a gluten-
free diet may stabilize the podocyte cytoskeleton, reducing
protein loss through the urine.63 Although these case reports
and case series show encouraging results, the full effects of
342
these strategies are not known to provide broad benefit to
all patients and should be reserved for patients with disease
that is difficult to manage. The limited number of patients
described in these studies increases the risk of confounding.
Additionally, the enrollment of patients with more severe
disease could bias the results or prevent a treatment effect
from being displayed in the data. Further and larger-scale
investigation is warranted, and a protocol for a trial using a
gluten-free, dairy-free diet in pediatric patients with NS at a
summer camp was published and is ongoing.65
Patients with NS may have additional complications,
such as line thromboembolism and infection. A detailed dis-
cussion of these complications is outside of the scope of this
review. However, these complications may have significant
implications for patients receiving nutrition support therapy
(ie, patients with vascular access devices).
Conclusion
NS is a complex pediatric kidney disease with many impli-
cations for nutrition support clinicians. Providing optimal
care for these patients requires attention to both nutrition
and pharmacologic therapies. Provision of energy, protein,
fluids, electrolytes, and micronutrients are patient specific
and based on the clinical status of the patient. Careful
attention to growth, bone development, and drug-nutrient
interactions can prevent complications and optimize care
for these patients.
Statement of Authorship
K. J. Hampson contributed to the conception, design,
acquisition, analysis, and interpretation of the article as
well as drafted and revised the manuscript. M. L. Gay
contributed analysis and interpretation of the article as
well as revised the manuscript. M. E. Band contributed
analysis and interpretation of the article as well as revised
the manuscript. All authors gave final approval and are
accountable for the aspects of work, including integrity and
accuracy.
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