N ephrotic Syn d ro me

Chia-shi Wang, MD, MSc*, Larry A. Greenbaum, MD, PhD

KEYWORDS
 Nephrotic syndrome  Edema  Peritonitis  Thrombosis  Minimal change disease
 Focal segmental glomerulosclerosis

KEY POINTS
 The classic features of nephrotic syndrome are edema, proteinuria, hypoalbuminemia,
and hyperlipidemia.
 Minimal change disease, the most common cause of nephrotic syndrome in childhood,
usually goes into remission within 4 weeks after starting corticosteroids, but there is a
high risk of relapse after corticosteroids are stopped.
 Focal segmental glomerulosclerosis is the most common diagnosis in children who do not
respond to corticosteroids, and it is an important cause of kidney failure in childhood.
 Complications of nephrotic syndrome include infections, including spontaneous bacterial
peritonitis and cellulitis, and blood clots due to hypercoagulability.
 Nephrotic syndrome may be secondary to gene mutations, especially in infants, or sys-
temic diseases, such as hepatitis or systemic lupus erythematosus.

INTRODUCTION

There are 4 classic features of nephrotic syndrome (Box 1).1 There are many different
causes of nephrotic syndrome (Table 1), but they share a common pathophysiology:
massive loss of protein in the urine due to a defect in the glomerular filtration barrier.2
The most common causes of nephrotic syndrome in childhood are idiopathic min-
imal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). The
excellent response to corticosteroids in most patients with MCD has led to the empiric
use of corticosteroids in most children with nephrotic syndrome, unless there are clin-
ical features or laboratory findings suggesting a different cause.3

Disclosure: C. Wang and L.A. Greenbaum have received funding from Mallinckrodt Pharmaceu-
ticals for an investigator-initiated clinical trial of H.P. Acthar Gel in childhood nephrotic syn-
drome. L.A. Greenbaum serves on the Data and Safety Monitoring Board for a clinical trial
sponsored by Retrophin in patients with nephrotic syndrome. L.A. Greenbaum is a co-
investigator of CureGN, an observational study of nephrotic syndrome patients sponsored by
the National Institutes of Health.
Division of Pediatric Nephrology, Department of Pediatrics, Emory University School of Medi-
cine and Children’s Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322-
1015, USA
* Corresponding author.
E-mail address: chia-shi.wang@emory.edu

Pediatr Clin N Am 66 (2019) 73–85

https://doi.org/10.1016/j.pcl.2018.08.006 pediatric.theclinics.com
0031-3955/19/ª 2018 Elsevier Inc. All rights reserved.
74 Wang & Greenbaum

Box 1
Classic features of nephrotic syndrome

Proteinuria
Hypoalbuminemia
Edema
Hyperlipidemia

There are a variety of ways of classifying nephrotic syndrome (Box 2), and a pa-
tient’s classification may change over time. For example, new knowledge may reveal
a genetic cause or a pathogenic pathway. The histology does not determine other
classifications: a patient with FSGS may have primary or secondary disease; genetic
or nongenetic cause; or steroid-sensitive or steroid-resistant disease.
Some patients with nephrotic syndrome may have nephritic features (hypertension,
hematuria, and decreased kidney function). Similarly, patients with a nephritic disease
may have nephrotic features. This article does not discuss diseases that rarely present
with nephrotic syndrome (eg, IgA nephropathy) or diseases that typically present with
nephritic syndrome, but may have nephrotic features (eg, postinfectious
glomerulonephritis).
For idiopathic nephrotic syndrome, response to corticosteroids is currently the best
predictor of disease outcome. Ongoing research attempts to integrate genetic, epige-
netic, molecular, and clinical data to determine a more precise disease taxonomy and
improve outcome prediction.4

CLINICAL EVALUATION

The evaluation of a child with nephrotic syndrome includes a history and physical ex-
amination targeted at identifying secondary causes and complications of the disease.
Diagnostic evaluation is dictated by the findings on history and physical examination
and the response to corticosteroids.

History
The age of the child with nephrotic syndrome dictates the most likely causes. Congen-
ital nephrotic syndrome (CNS; presentation during the first 3 months of life) most
commonly has a genetic cause (see later discussion), but may be secondary to a
congenital infection. Infantile nephrotic syndrome (3–12 months of age at presenta-
tion) is also likely to be genetic.5–7 Idiopathic nephrotic syndrome most commonly pre-
sents between ages 2 and 7 years, and there is a male predominance (up to 3.8:1
male-to-female ratio).8 Most of these children have MCD that is responsive to cortico-
steroids, although steroid-resistant disease, typically idiopathic FSGS, can also occur.
In older children, and especially in adolescents, MCD becomes less common, and pri-
mary FSGS, membranous nephropathy (MN), and membranoproliferative glomerulo-
nephritis (MPGN) are more common than in younger children.2 Older children and
adolescents are also at increased risk for secondary causes (eg, systemic lupus ery-
thematosus [SLE], hepatitis B and C, human immunodeficiency virus [HIV]).9
A family history of nephrotic syndrome, FSGS, chronic kidney disease, or consan-
guinity should prompt consideration of a genetic cause. Autosomal recessive and
autosomal dominant disease typically present in younger children and adolescents,
respectively. A genetic cause should also be considered if there are congenital anom-
alies, such as occur in a variety of syndromic disorders (see Table 1).10
 Nephrotic Syndrome 75

Table 1
Classification and causes of nephrotic syndrome in childhood

Examples of genetic disorders (associated gene) Common age at presentation

Finnish-type congenital nephrotic syndrome (NPHS1) Infancy
Diffuse mesangial sclerosis (eg, PLCE1, WT1) Infancy
Early-onset autosomal recessive SRNS Infancy and early childhood
(eg, NPHS2, PLCE1)
Late-onset SRNS (eg, ACTN4, TRPC6) Late childhood and adolescence
Examples of syndromic genetic disorders
(associated gene)
Denys-Drash and WAGR (WT1) Infancy
Schimke immuno-osseus dysplasia Childhood
(SMARCAL1)
Pierson syndrome (LAMB2) Infancy
Galloway-Mowat syndrome Infancy
(eg, WDR73 and LAGE3)
Frasier syndrome (WT1) Childhood or adolescence
Idiopathic (histologic classification)
MCD Early childhood to adolescence
FSGS Early childhood to adolescence
MN Late childhood and adolescence
MPGN Late childhood and adolescence
Rheumatologic
SLE Late childhood and adolescence
Infections
Hepatitis B, C Variable; infancy for
congenital exposure
HIV-1 Variable
Malaria Variable
Congenital syphilis, toxoplasmosis Infancy
Drugs/toxins
Penicillamine Variable
Gold Variable
Nonsteroidal anti-inflammatory drugs Variable
Pamidronate Variable
Interferon Variable
Mercury Variable
Heroin Variable
Lithium Variable
Malignancy
Lymphoma Variable
Leukemia Variable
Glomerular hyperfiltration
Sickle-cell disease Adolescence
Oligomeganephronia Adolescence
Morbid obesity Adolescence

Abbreviations: FSGS, focal segmental glomerulosclerosis; HIV-1, human immunodeficiency virus

type 1; MCD, minimal change disease; MN, membranous nephropathy; MPGN, membranoprolifer-
ative glomerulonephritis; SLE, systemic lupus erythematosus; SRNS, steroid-resistant nephrotic syn-
drome; WAGR, Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability.
Data from Refs.2,5,45
76 Wang & Greenbaum

Box 2
Classifications of nephrotic syndrome

Age of presentation
Congenital (first 3 months of life)
Infantile (4–12 months)
Childhood (>12 months)
Idiopathic versus secondary
Genetic versus acquired
Histology (eg, MCD, FSGS)
Steroid-sensitive versus steroid-resistant

The history should include questions about symptoms of lupus (joint pain, stiffness,
and swelling; rash; photosensitivity; mouth ulcers; hair loss; fevers; and malaise),
medication exposures (see Table 1); risk factors for or symptoms suggestive of infec-
tions that may cause nephrotic syndrome (ie, hepatitis B or C, HIV). Lymphadenopa-
thy, pallor, fevers, and fatigue may suggest malignancy, which is a very rare cause of
nephrotic syndrome in childhood.2
Patients typically present with insidious onset of edema, which may not be detected
until significant fluid accumulation has occurred (Fig. 1). The edema is gravity depen-
dent, and thus periorbital edema, occasionally misdiagnosed as allergies, is more
prominent in the morning. After daytime ambulation, edema becomes more noticeable
in the feet and legs. Scrotal, penile, and labial edema can be particularly distressing.
Although the chief complaint in nephrotic syndrome is usually edema, other clinical
presentations may occur:
 Incidental finding on urinalysis or when screening due to a positive family history
 Complication of nephrotic syndrome (see later discussion)
 Blood clot (pulmonary embolus [Fig. 2], deep venous thrombosis, arterial
thrombosis)
 Spontaneous bacterial peritonitis
 Cellulitis
 Abdominal pain due to bowel wall edema or hypoperfusion11

Fig. 1. Bilateral lower extremity edema in a patient with nephrotic syndrome with indenta-
tions visible bilaterally after applying pressure with a thumb.
 Nephrotic Syndrome 77

Fig. 2. Computed tomography angiography of the chest showing a right main pulmonary
artery embolus (red arrow) in a child with nephrotic syndrome. (Courtesy of Stephen Simo-
neaux, MD, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA.)

Physical Examination
Edema is the dominant finding; the location of the most prominent edema can be quite
variable between children. Rarely, the edema may be subtle despite massive protein-
uria. The examination should include looking for findings suggestive of a syndromic
condition, malignancy, or SLE (see earlier discussion) or complications of nephrotic
syndrome (blood clot, peritonitis, or cellulitis). Hypertension may be present, espe-
cially in patients with FSGS or MPGN.2
Diagnostic Evaluation
The initial evaluation of a child with suspected nephrotic syndrome should establish
the diagnosis of nephrotic syndrome (Box 3). Additional testing should screen for
the most likely causes and complications.
Evaluations Done in All Patients
 Complete blood count: Elevated hemoglobin may occur due to hemoconcentra-
tion from intravascular volume contraction from fluid moving into the interstitial
space.12 Anemia may be present if there is chronic kidney disease or a second-
ary cause (SLE or malignancy). Depression of white cells or platelets also raises
concerns of SLE or malignancy.
 Chemistries: Hyponatremia, typically mild, is a common finding due to secretion
of antidiuretic hormone secondary to intravascular volume depletion.12 Serum

Box 3
Laboratory testing to establish the diagnosis of nephrotic syndrome

Serum albumin 2.5 mg/L

Proteinuria
Random UPCR 2 mg/mg
24-h urine with greater than 50 mg/kg/day or greater than 40 mg/h/m2 protein
Hyperlipidemia (elevated cholesterol and/or triglycerides)

Abbreviation: UPCR, urine protein to creatinine ratio.

Data from Lombel RM, Gipson DS, Hodson EM. Kidney disease: improving global outcomes.
Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr Neph-
rol 2013;28(3):415–26.
78 Wang & Greenbaum

total calcium is low due to the low serum albumin since w50% of calcium nor-
mally binds to albumin. The ionized calcium is typically normal, but may be
low, possibly due to urinary loss of 25-hydroxyvitamin D.13
 Creatinine: Kidney function is usually normal in idiopathic nephrotic syndrome,
although it may be diminished if there is significant intravascular volume deple-
tion. Elevated serum creatinine not related to intravascular volume depletion is
more common with FSGS and in secondary nephrotic syndrome.14
 Complement levels: Low C3 is common in MPGN; C3 and C4 are typically low in
lupus nephritis. A low C3 is also consistent with postinfectious glomerulone-
phritis, which may occasionally be confused with idiopathic nephrotic
syndrome.15
 Chest radiograph: This may rarely detect evidence of malignancy. Small pleural
effusions are almost universally present and do not require intervention.16
Evaluations Done in Select Patients
 Antinuclear antibody: Screens for SLE in older children and adolescents or if
there are signs and symptoms suggestive of SLE. Additional serologies for
SLE may be indicated if suspicion is high.
 Viral testing (HIV, hepatitis B and C): Screen in children with CNS, older children,
and adolescents or if biopsy findings suggest infection as a possible cause.7
 Kidney biopsy: A kidney biopsy is done in patients with steroid-resistant disease,
older adolescents, or patients with other findings suggestive of a cause other
than MCD. Although previously done in CNS, rapid genetic testing may make
this unnecessary.1
 Genetic testing: This is most useful in congenital and infantile nephrotic syn-
drome, syndromic disease, familial disease, or if there is a history of consanguin-
ity. Genetic testing is increasingly used in children with steroid-resistant
disease.10
 Histology-specific testing: There are specific additional tests that should be
considered in patients diagnosed with MN and MPGN (see later discussion).

COMPLICATIONS
Infections
Infections are common in children with nephrotic syndrome. Infections are due to uri-
nary loss of immunoglobulins and complement factors, impaired lymphocytic func-
tion, treatment with immunosuppressive agents, ascites, and edema. Infections
include pneumonia, bacteremia, spontaneous bacterial peritonitis, and cellulitis,
with increased susceptibility to encapsulated organisms such as Streptococcus
pneumoniae.2,17,18
Acute Kidney Injury
Acute kidney injury (AKI) is commonly due to intravascular volume depletion, which
may be exacerbated by diuretics if concurrent intravenous replacement of albumin
is not performed. AKI is more likely in children with steroid-resistant disease, concom-
itant infections, and nephrotoxic medication exposure.19
Thromboembolism
Thromboembolism is estimated to occur in approximately 3% of childhood
nephrotic syndrome patients, with venous clots accounting for 97% of the cases.20
The hypercoagulability in nephrotic syndrome is multifactorial: increased platelet
aggregability, increased synthesis of prothrombotic factors, and urinary loss and
 Nephrotic Syndrome 79

decreased levels of antithrombin III, protein C, and protein S.21 Traditional risk fac-
tors, such as heritable thrombophilia, intravascular volume depletion, and use of
central venous catheters further increase the risk. Presenting complaints include
asymmetric limb swelling, central venous catheter malfunction, gross hematuria
(renal vein thrombosis), superior vena cava syndrome, and respiratory compromise
(pulmonary embolism).20

CAUSES
Minimal Change Disease and Primary Focal Segmental Glomerulosclerosis
Epidemiology and clinical presentation
MCD and FSGS are the causes of more than 80% of idiopathic nephrotic syndrome
cases in childhood, with MCD occurring more frequently than FSGS.22 The prevalence
of FSGS increases with age; the median age of onset is 6 years for FSGS and 3 years
for MCD.8 FSGS is present in 20% to 30% of adolescents presenting with nephrotic
syndrome and is more common in Hispanic and black patients.2
On initial presentation, it is not possible to distinguish between MCD and FSGS,
although microscopic hematuria, hypertension, and elevated serum creatinine occur
more frequently with FSGS.8 Approximately 80% of patients with suspected idiopathic
childhood nephrotic syndrome have resolution of proteinuria within 8 weeks when
treated with high-dose oral corticosteroids.1 Failure to respond to corticosteroids is
predictive of non-MCD histology; approximately 92% of MCD patients respond to cor-
ticosteroids and half of non-responders have FSGS. Approximately 70% of FSGS pa-
tients do not respond to corticosteroid therapy.22 Thus, a biopsy is recommended for
those who fail to respond to an adequate course of corticosteroid therapy.3
Pathophysiology
By definition, the cause of idiopathic MCD and FSGS is unknown. There is ongoing
debate whether MCD and FSGS represent a spectrum of the same disease or are
separate diseases.23 There is convincing evidence that the podocyte is the target
cell in these diseases. Based on the clinical response to corticosteroids and other
immunosuppressive agents, it is hypothesized that there is an underlying immune
mechanism leading to podocyte dysfunction, but proof of this hypothesis remains
elusive.2 However, there is also evidence for a direct effect of some medications on
the podocyte.24,25
Disease course and prognosis
Steroid response is the most important predictor of prognosis. Long-term prognosis is
good for patients who are responsive to corticosteroid therapy, with greater than 80%
of patients no longer experiencing disease relapses at 8 years following disease
onset.26 Frequent disease relapses occur in approximately 60% of patients, causing
morbidity from disease complications and treatment side effects.2 Prognosis among
steroid-resistant patients—the minority of MCD and majority of FSGS patients—is
much less promising. Those who are refractory to treatment have a greater than
50% risk of progression to end-stage renal disease (ESRD) within 5 years of diag-
nosis.3 In fact, FSGS is the second leading diagnosis among pediatric dialysis patients
in North America.27
Treatment
The treatment of the initial episode of nephrotic syndrome is oral prednisone at 60 mg/
m2/day or 2 mg/kg/day (maximum 60 mg/day) for 4 to 6 weeks, followed by 40 mg/m2
or 1.5 mg/kg (maximum 40 mg/day) on alternate days for 1 to 2 months. Daily predni-
sone is given for relapses and is reduced to alternate day dosing once the urine is
80 Wang & Greenbaum

negative or trace for protein for 3 days.1,3 For patients with frequent relapses, espe-
cially if there are significant steroid side effects, a variety of agents are used to prevent
relapses: alkylating agents, calcineurin inhibitors, mycophenolate mofetil, and rituxi-
mab.28 Home urine monitoring for relapses is a critical component of management.29
The recommended treatment of steroid-resistant patients is a minimum 6-month
course of a calcineurin inhibitor and an angiotensin converting enzyme inhibitor
(ACEi) or angiotensin II receptor blocker (ARB). Evidence for other therapeutic ap-
proaches is limited.28

Membranous Nephropathy
Epidemiology and clinical presentation
MN is uncommon in childhood. Secondary causes include SLE, hepatitis B, drugs,
and toxins. Idiopathic MN causes approximately 1.5% of childhood nephrotic syn-
drome.8 In MN secondary to SLE, typical age of onset is around 13 years, with female
predominance; AKI, hematuria, and hypertension can be seen on presentation.30,31
The mean age at presentation for idiopathic MN in childhood is around 10 years
with a slight male predominance. Microscopic hematuria is common, and gross hema-
turia may also occur. Hypertension is less common.32

Pathophysiology
A major advancement in the understanding of the pathogenesis was the discovery of
antiphospholipase A2 receptor (PLA2R) antibodies in patients with MN. PLA2R is a
transmembrane glycoprotein expressed by the podocyte. Circulating anti-PLA2R au-
toantibodies are found in 70% of primary adult MN patients and levels correlate with
disease activity; screening for autoantibodies has thus become an important compo-
nent of management.32 Autoantibodies against other glomerular antigens may also
cause primary MN.33,34

Disease course and prognosis

The degree of proteinuria is an important prognostic indicator in idiopathic MN. Pa-
tients with proteinuria without complete features of nephrotic syndrome often achieve
disease remission spontaneously, although relapses can occur. Those with nephrotic
syndrome have a 50% remission rate, with renal dysfunction developing in approxi-
mately one-third of the patients.32 In addition, age greater than 10 years, hypertension
on presentation, and presence of renal venous thrombosis are poor prognostic indica-
tors.35,36 Prognosis in secondary MN depends on the cause.

Treatment
Treatment of secondary MN depends on the cause and will not be reviewed here. Data
on treatment of idiopathic MN in children are limited given its low incidence. Children
without nephrotic syndrome are generally given ACEis/ARBs and other supportive
therapy without immunosuppressants. Those with nephrotic syndrome, especially if
decreased kidney function or fibrosis on biopsy, may be treated with alkylating agents,
calcineurin inhibitors, or rituximab, with limited evidence on the optimal approach in
children.32

Membranoproliferative Glomerulonephritis, C3 Glomerulopathy, and

Immune-Complex–Mediated Membranoproliferative Glomerulonephritis
Epidemiology and clinical presentation
MPGN is a clinically diverse group of diseases traditionally grouped together based on
common histologic findings. A key serologic feature is low C3, seen in 80% to 95% of
the patients.37 MPGN is further subdivided based on the location of immune deposits:
 Nephrotic Syndrome 81

type 1 (subendothelial), type 2 (also called dense deposit disease [DDD]; intramembra-
nous deposits), and type 3 (subendothelial and subepithelial). This histologic classifi-
cation offers limited information on the underlying disease process due to extensive
overlap. Thus, a new classification is based on whether the immune complexes are
predominantly composed of C3 (C3 glomerulopathy [C3G]) or immunoglobulins (im-
mune-complex-mediated MPGN [IC-MPGN]). C3G is further subdivided based on
the location and quality of deposits into DDD or C3 glomerulonephritis (C3GN). The
new classification improves diagnostic precision, but is imperfect.38
The incidence of MPGN or C3G/IC-MPGN is estimated to be 2 cases per 106 chil-
dren, comprising approximately 7.5% of nephrotic syndrome cases in pediatrics.
Onset is typically in late childhood or adolescence, with a slight male predominance.8,37
Nearly half of patients present with isolated hematuria and proteinuria that is found on
routine evaluation. About one-third of patients present with nephrotic syndrome, usu-
ally accompanied by microscopic hematuria. Others present with gross hematuria with
acute nephritic syndrome, often associated with rapidly progressive glomerulone-
phritis. Hypertension and renal insufficiency can be seen on presentation.39

Pathophysiology
Table 2 summarizes causes of C3G and IC-MPGN and the associated traditional his-
tologic classification. IC-MPGN is most commonly secondary to chronic infections,
autoimmune disorders, or malignancies. In chronic infections and autoimmune disor-
ders, antigen-antibody immune complexes trigger classical complement pathway-
medicated injury. The monoclonal immunoglobulins formed in malignancies, which
are rare in childhood, also trigger the classical complement pathway, resulting in
IC-MPGN. C3G is generally thought to be caused by abnormalities in the alternative
complement pathway, due to either mutations in genes for complement or comple-
ment regulatory proteins or autoantibodies against complement system components,
leading to uncontrolled activity and complement-mediated damage of glomeruli.

Table 2
Causes and traditional histologic classification of immune-complex-mediated
membranoproliferative glomerulonephritis and C3 glomerulopathy

Traditional
Causes Classification
IC-MPGN
Infections: hepatitis B, hepatitis C, staphylococcus, Mycobacterium Type 1
tuberculosis, Propionibacterium acnes, brucella, Coxiella burnetii,
streptococci, nocardia, meningococcus, malaria, schistosomiasis,
HIV
Autoimmune: SLE, mixed cryoglobulinemia, Sjögren syndrome, Type 1
scleroderma
Malignancy: monoclonal gammopathy, chronic lymphocytic leukemia, Type 1
low-grade B-cell lymphoma, multiple myeloma
C3G
Dysregulation of the alternative complement pathway: mutations in Type I, II,
complement-regulating proteins (CFH, CFI, CFHR5), autoantibodies to and III
complement-regulating proteins (anti-C3bBb, anti-CFH, anti-CFI,
anti-CFB), C3 mutations

Abbreviations: C3G, C3 glomerulopathy; IC-MPGN, immune-complex-mediated membranoproli-

ferative glomerulonephritis; SLE, systemic lupus erythematosus.
Data from Refs.38,40,47,48
82 Wang & Greenbaum

There is, however, some overlap between IC-MPGN and C3G, and the association of
IC-MPGN with the classical complement system and C3G with the alternative comple-
ment system may not be absolute.38,40

Disease course and prognosis

Long-term outcome for MPGN (C3G and IC-MPGN) is poor. Fifty percent and 90%
develop ESRD by 10 years and 20 years, respectively. Outcome is worse in those pre-
senting with nephrotic syndrome, renal insufficiency, and crescents on initial biopsy.
C3G may be more refractory to treatment than IC-MPGN.37,41

Treatment
There is limited evidence to guide therapy in C3G and IC-MPGN. Corticosteroids,
mycophenolate mofetil, and rituximab have been used, along with ACEis/ARBs,
without consistent efficacy. More recently, targeted complement pathway inhibitors
have been evaluated in patients with C3G, but benefit still needs to be
established.42,43

Congenital Nephrotic Syndrome

Cause and clinical presentation
CNS, defined as nephrotic syndrome presenting in the first 3 months of life, is rare.
Secondary causes include congenital infections (syphilis, toxoplasmosis, cytomegalo-
virus, rubella, HIV), infantile SLE, and fetomaternal alloimmunization. Screening for
congenital infections is an important component of the evaluation of the infant with
CNS. CNS is most commonly caused by mutations in genes encoding proteins that
are essential for proper function of the glomerular filtration barrier. CNS of the Finnish
type is caused by mutations in the gene (NPHS1) encoding nephrin, a protein that is a
critical component of the slit diaphragm between glomerular podocytes. Mutations in
multiple other genes may cause CNS (Box 4).44
Presentation differs depending on the mutation involved. Patients with NPHS1 mu-
tations typically present with nephrotic syndrome in the first weeks of life, with massive
proteinuria that is associated with worse outcomes, although milder forms exist. An
enlarged placenta is classically observed at birth (>25% of the infant’s birth weight).
NPHS2 mutations typically present after 1 month of life, with many cases presenting
in early childhood. Children with syndromic causes of CNS have extrarenal
manifestations:
 Urogenital abnormalities with WT1 mutations in Denys-Drash syndrome
 Eye defects with LAMB2 mutations in Pierson syndrome
 Neurologic findings in Galloway-Mowat syndrome10,45

Box 4
Examples of genes and associated proteins where mutations may cause congenital nephrotic
syndrome

NPHS1 (nephrin)
NPHS2 (podocin)
WT1 (Wilms tumor protein)
LAMB2 (laminin)
PLCε1 (phospholipase C epsilon 1)

Data from Machuca E, Benoit G, Nevo F, et al. Genotype-phenotype correlations in non-Finnish

congenital nephrotic syndrome. J Am Soc Nephrol 2010;21(7):1209–17.
 Nephrotic Syndrome 83

Prognosis
Secondary CNS generally resolves with treatment of the underlying cause or after
disappearance of maternal autoantibodies. Primary CNS is generally not responsive
to treatment and progresses to ESRD. Classic Finnish-type CNS patients frequently
reach ESRD by 2 to 3 years. In contrast, patients with mutations in podocin generally
develop ESRD between 6 and 9 years.44 CNS is complicated by failure to thrive, infec-
tions, and thrombosis.6,46
Treatment
Goals of treatment are to control edema with a combination of albumin infusions and
diuretics and to prevent and treat complications such as infections and thromboem-
bolism. Nutritional support and thyroxine and cholecalciferol to replace urinary losses
are important to promote growth and development. Children eventually need kidney
transplantation, which is commonly preceded by nephrectomies to address hyperco-
agulability and hyperlipidemia if the patient remains nephrotic.11

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