Seminar

Idiopathic nephrotic syndrome in children

Damien G Noone, Kazumoto Iijima, Rulan Parekh

The incidence of idiopathic nephrotic syndrome (NS) is 1∙15–16∙9 per 100 000 children, varying by ethnicity and Published Online
region. The cause remains unknown but the pathogenesis of idiopathic NS is thought to involve immune June 14, 2018
http://dx.doi.org/10.1016/
dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. Genetic risk is more S0140-6736(18)30536-1
commonly described among children with steroid-resistant disease. The mainstay of therapy is prednisone for the Department of Paediatrics,
vast majority of patients who are steroid responsive; however, the disease can run a frequently relapsing course, University of Toronto, Toronto,
necessitating the need for alternative immunosuppressive agents. Infection and venous thromboembolism are the ON, Canada
main complications of NS with also increased risk of acute kidney injury. Prognosis in terms of long-term kidney (D G Noone MB BCh BAO,
Prof R Parekh MD); Division of
outcome overall is excellent for steroid-responsive disease, and steroid resistance is an important determinant of Nephrology, The Hospital for
future risk of chronic or end-stage kidney disease. Sick Children, Toronto, ON,
Canada (D G Noone, R Parekh);
Introduction might have minimal change or focal segmental Department of Pediatrics, Kobe
University Graduate School of
Nephrotic syndrome (NS) is characterised by the triad of glomerulosclerosis (FSGS). Owing to the heterogeneity of Medicine, Kobe, Japan
proteinuria, hypoalbuminaemia, and oedema (panel 1). SRNS, only 50% are at risk of progressing to ESRD in (K Iijima MD); Child Health
Many glomerular disorders in childhood present with 5 years; typically those children who do not achieve Evaluative Sciences, Research
nephrotic syndrome, however, the vast majority are complete or partial remission.14 Long-term prognosis in Institute, Hospital for Sick
Children, Toronto, ON, Canada
idiopathic NS, and the focus of this Seminar (panel 2). adults with paediatric onset NS is not well studied and (R Parekh); University Health
The precise cause of this common childhood disease would provide important information on risk for families. Network, Toronto, ON, Canada
remains elusive despite substantial advances in our Standard definitions are established and highlighted in (R Parekh); and Dalla Lana
understanding of podocyte biology. Idiopathic NS can the 2012 Kidney Disease Initiatives: Global Outcomes School of Public Health, and
Health Policy, Management
be classified on the basis of response to steroid therapy, (KDIGO; panel 1).1 and Evaluation, University of
pattern of relapse, histopathology, or by genetic Toronto, Toronto, ON, Canada
mutations. Most simply, NS is categorised on the basis Clinical presentation (R Parekh)
of clinical response to steroid therapy, as steroid Classically, a child presents with a history of progressive Correspondence to:
sensitive (SS) or steroid resistant (SR). Although helpful oedema, initially periorbital and noticeable in the Dr Rulan Parekh, The Hospital for
Sick Children, Toronto,
for guiding therapy, this classification lends very little morning. There can be an antecedent infection, typically ON M5G 1X8, Canada
understanding to disease mechanism. Idiopathic NS of the upper respiratory tract. Urine output is described [email protected]
is best defined as a podocytopathy due to loss or as frothy or foamy. Abdominal pain is relatively common
altered function of the podocytes, resulting in massive and, if accompanied by fever, could signify spontaneous
proteinuria. bacterial peritonitis. Headache with accompanying
The mainstay of treatment for NS is corticosteroids neurological signs or irritability should raise the
(steroids) with protocols largely based on seminal studies suspicion for cerebral venous sinus thrombosis. Clinical
from the International Study of Kidney Disease in investigations are summarised in panel 3.
Children and the Arbeitsgemeinschaft für Pädiatrische
Nephrologie.2,3 Steroid responsiveness and frequency Pathology
of relapses provide the best guide to therapy in Most children do not get a kidney biopsy at presentation.
idiopathic NS. The majority of children respond well to Historical studies have demonstrated that the most
steroids within 4 weeks (steroid-sensitive NS [SSNS]);
however, most will relapse, with approximately half
becoming frequent relapsers or steroid dependent.4,5 Search strategy and selection criteria
Although historically fewer than 10% of children We conducted a systematic literature search of published
with SSNS continue to have relapses in adulthood,3,6 literature using Cochrane, PubMed, Embase, and MEDLINE.
contemporary cohorts suggest higher proportions of Key search terms included “children”, “nephrotic
16∙4–42%. Frequency of relapses during childhood and syndrome”, “steroid sensitive nephrotic syndrome”, “steroid
the need for non-steroid immuno­suppressants such as resistant nephrotic syndrome” and “focal segmental
cyclophosphamide or ciclosporin are predictive of active glomerulosclerosis”. The reference lists of all included
disease as young adults.7–-10 Among 287 children followed papers and review articles were also cross-referenced to
up for over 15 years, 85% achieved long-term remission.11 identify additional relevant studies. The search was not
Despite ongoing relapses, kidney outcomes remain limited by study design, year of publication, or language
excellent, with risk of progression to chronic kidney but precedence was given where possible to randomised
disease estimated to be less than 5% in those with SSNS controlled trials and studies from the last 5 years. The initial
at 10 years after diagnosis.12 In contrast, SRNS is search was done on Nov 29, 2015 and repeated on Dec 1,
associated with increased risk of progression to end-stage 2017 to update with the recent published clinical trials.
renal disease (ESRD).13 Children with SRNS on biopsy

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 Seminar

Panel 1: Relevant definitions in nephrotic syndrome1 Panel 2: Causes of non-idiopathic childhood nephrotic
syndrome (NS)
Nephrotic syndrome (NS)
Oedema with protein excretion >40 mg/m² per h or urine • Nephritic/nephrotic glomerular disorders
protein:creatinine ratio ≥2000 mg/g (≥200 mg/mmol) or • IgA nephropathy and Henoch–Schonlein purpura
>3+ proteinuria on dipstick with serum albumin <2∙5 g/dL • Membranoproliferative glomerulonephritis
(25 g/L) • Lupus nephritis
• Postinfectious glomerulonephritis
Remission
• Immune complex mediated glomerulopathy
Urine albumin trace or negative on dipstick or proteinuria
• C1q nephropathy
<4 mg/m² per h or urinary protein:creatinine ratio <200 mg/g
(20 mg/mmol) for 3 consecutive days • Thin basement membrane disease
Relapse • Membranous nephropathy
Urine albumin 3+ or 4+ or proteinuria >40 mg/m² per h or
• Sickle-cell nephropathy
urinary protein:creatinine ratio >200 mg/g (20 mg/mmol) for
3 consecutive days • Thrombotic microangiopathy
Frequently relapsing NS • Interstitial nephritis
≥2 relapses within 6 months of initial response or ≥4 in any
• Infections associated with NS
12 month period
• Hepatitis B and C
Steroid-dependent NS • HIV-1
2 consecutive relapses occurring while weaning to alternate • Malaria
day steroids or within 2 weeks of steroid discontinuation • Syphilis
• Toxoplasmosis
Steroid-resistant NS
• Varicella zoster
Persistent proteinuria despite 60 mg/m² or 2 mg/kg for
8 weeks, after ensuring no infection or non-adherence to • Drugs associated with NS
medication • Non-steroidal anti-inflammatory drugs
• Bisphosphonates
common pathological findings in childhood NS are • d-penicillamine
either classified as minimal change and termed • Heavy metals (mercury and gold)
minimal change disease (MCD) or FSGS.1 In minimal • Lithium
change, the glomeruli appear normal under light • Rifampicin
microscopy, with evidence of podocyte effacement by • Sulfasalazine
electron microscopy.17 Characteristic histology in FSGS • T-cell-related malignancy
is segmental sclerosis of affected glomeruli, with the • Hodgkin’s lymphoma
segment often adherent to Bowman’s capsule by • Thymoma
synechiae.18 • Leukaemia

Incidence
There is considerable variation in incidence of NS in south Asian children, FSGS is reported less
depending on country of origin, or ethnicity, with commonly and ranges from 15 to 39%.19
proportions ranging from 1∙15 to 16∙9 per
100 000 children (figure 1).11,19 Incidence is highest in Pathophysiology
those of south Asian ancestry compared to European Abnormalities in the podocyte and glomerular filtration
ancestry as reported in studies from the UK, barrier
South Africa, and Canada. Incidence of steroid- The podocyte is a polarised epithelial cell with inter­
resistance ranges from 2∙1 to 27∙3% and also varies by digitating foot processes with a unique cell–cell junction
country of origin (figure 1).19 Most studies are known as the slit diaphragm. Along with the glomerular
retrospective or cross-sectional with only a few basement membrane and the fenestrated glomerular
longitudinal studies. Reported differences can thus be endothelium, the podocyte forms a trilayered structure—
partially attributable to management variations across the glomerular filtration barrier. The podocyte and
practices or regions, as well as use of differing filtration barrier allow an ultrafiltrate almost completely
definitions of outcomes. African–American children devoid of protein to pass into the Bowman’s space and
are more likely to have biopsy-proven FSGS (42–72%)19 proceed onto the proximal tubule. Podocyte architecture
and have the highest proportion of progression to is maintained by an extensive actin cyto­ skeleton that
ESRD as compared to European Americans,20 whereas enables the glomerular filtration barrier to withstand the

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 Seminar

Panel 3: Investigations in a child with nephrotic syndrome A

(NS) City, country Ethnicity (n)
New Zealand Multi-ethnic (n= 49)*
Baseline investigations Australia Not specified (n=135)
1 Urinalysis and urine microscopy The Netherlands Not specified (n=231)
2 Urine albumin or protein:creatinine ratio
Kentucky, USA Not specified (n=34)
3 24-h timed collection of urine for protein quantification
Benghazi, Libya Arabs (n=134)
4 Serum electrolytes, albumin, total protein, renal function,
Farwaniya/Jahra, Kuwait Arabs (n=55)
and cholesterol
Ohio, USA African-Americans (n=15)
Additional testing if there is a suspicion of a Whites (n=157)

glomerulonephritis Kansas City, USA African-Americans (n=25)

Europeans (n=54)
1 Serum complement C3 and C4 concentrations
Erie county, USA Whites (n=9)
2 Serum immunoglobulins
Non-whites (n=73)
3 Antistreptolysin titres
Birmingham, UK Afro-Caribbeans (n=2)
4 Anti-DNAse B antibodies Europeans (n=15)
5 Antinuclear antigen antibodies Asians (n=27)
6 Anti-double-stranded DNA antibodies Former Yorkshire, UK Non-Asians (n=49)†
7 Anti-neutrophil cytoplasmic antibodies Asians (n=121)†
Leicestershire, UK Non-Asians (n=22)
Infectious work-up depending on clinical context Asians (n=21)
1 Hepatitis B and C, HIV, syphilis, or tuberculosis can also be Toronto, Canada East/Southeast Asians (n=69)
considered depending on the clinical context South Asians (n=237)
Europeans (n=173)
Consideration of genetic testing Others (n= 232)
1 A positive family history of NS 0 2 4 6 8 10 12 14 16 18
2 Congenital NS Incidence‡ (per 100 000 people)
3 Infantile onset (<1 year)
4 Failure to respond to steroid therapy B
Steroid resistant Steroid sensitive
5 Persistent kidney dysfunction
City, country Ethnicity (total n, SR%)§
6 Features suggestive of a known syndrome (appendix)15
New Zealand Multi-ethnic (n=49, 19·6%)
Renal biopsy considered in the following situations Durban, South Africa Black and Indian (n=816, 27·3%)
1 Age <1 or >12 years
Diyarbakir, Turkey Turkish (n=138, 13·2%)
2 Persistent or sustained elevation in creatinine
Sindh, Pakistan Pakistani (n=538, 31·1%)
3 Significant haematuria or gross haematuria16
Siem Reap, Cambodia Cambodian (n=112, 6·2%)
4 Hypocomplementaemia
Poland Polish (n=178, 24·7%)
5 Findings indicative of another autoimmune disease
Boston and New York, European (n=65, 6·2%)
6 Infection with hepatitis B or C, HIV, or tuberculosis
USA Black and Hispanic
7 Hypertension (n=177, 15·3%)
8 Glucocorticoid resistance New Orleans, USA African-American (n=96, 11·0%)
Caucasian (n=103, 3·6%)
Toronto, Canada Others (n=232, 2·6%)
substantial capillary hydrostatic pressure. Loss of normal East/Southeast Asians
podocyte structure, the foot processes or the slit (n=66, 4·5%)
diaphragm that spans these interdigitations can lead to South Asians (n=237, 2·1%)

loss of albumin in the ultrafiltrate. Podocytes are Europeans (n=173, 6·8%)

terminally differentiated cells with minimal regeneration 0 10 20 30 40 50 60 70 80 90 100

and thus, vulnerable to injury. %
Complete effacement of the podocyte with the loss of
Figure 1: Incidence of childhood nephrotic syndrome per 100 000 persons by ethnicity, reported from
normal architecture results in massive proteinuria, a 1946 to 2014 (A) and variability of steroid responsiveness by ethnicity among children with nephrotic
hallmark of nephrotic syndrome (figure 2). The syndrome in reported studies from 1986 to 2014 (B)
pathogenesis leading to podocyte effacement is not clear Published with permission from Ethnic differences in childhood nephrotic syndrome, published in Frontiers in
Pediatrics, 2016.19 n=total number of patients; SR%=proportion of steroid resistance. *New Zealand European,
in idiopathic NS, nor the specific mechanism in
Maori, Pacific Island, Asian, Other. †Only those with steroid-sensitive nephrotic syndrome. ‡Estimated on the basis
which treatment with steroids leads to the recovery of of data in published studies.
podocyte structure and function. Systemic factors,
immune mediated or circulating, can contribute to familial forms of nephrotic syndrome underscores
podocyte effacement, but there is no single uni­ the importance of genetic variants leading to specific
fying hypo­ thesis. Supporting evidence from rare or podocyte abnormalities.

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 Seminar

Congenital and steroid-resistant forms of NS are podocyte structure and function is dependent on
associated with mutations in genes encoding com­ the molecular interplay between the network of
ponents of the slit diaphragm, podocyte actin cyto­ proteins that anchor the podocyte to the glom­
skeleton, podocyte mitochondrial proteins, lysosomal erular basement membrane and maintain its unique
proteins, nuclear transcription factors, and glomerular structure, and also the crosstalk with the fenestrated
basement membrane (figure 2).21 Maintenance of glomerular endothelium. Thus, any injury to the
Figure 2: The glomerular
filtration barrier and
pathogenesis of idiopathic Glomerular filtration barrier in nephrotic syndrome
nephrotic syndrome Kidney Nephron Glomerulus
Within the kidney is the
glomerulus, a capillary tuft that
filters the blood. The podocyte,
glomerular basement
Glomerular
membrane and the fenestrated filtrate
glomerular endothelium
comprise the glomerular
filtration barrier allowing the
ultrafiltrate to enter the urinary Afferent
space. The podocyte has capillary
extensive cellular extensions
that interdigitate and these Efferent
capillary
foot processes are connected by
the slit diaphragm. In nephrotic
syndrome, there is extensive Normal Nephrotic syndrome
effacement of the podocytes Pathogenesis
and loss of this barrier to (a) Immune-mediated
protein, allowing excessive (b) Systemic circulating factors (eg, suPAR)
serum albumin to leak into the (c) Podocyte related factors (eg, ANGPTL4)
urine. The pathogenesis of (d) Genetic variants
idiopathic nephrotic syndrome
Mutant proteins play roles in:
is hypothesised to be either
immune-mediated, owing to a 1 Nucleus 4 Actin
systemic podocyte-derived Urinary space 2 Mitochondria 5 Slit diaphragm
circulating factor, or, in rarer or
familial forms, a genetic variant. 3 Lysosomes 6 Basement membrane
Numerous mutations are Podocyte
associated with steroid- cell body
resistant nephrotic syndrome
that affect various parts of the
podocyte itself, or the other 1
constituents of the glomerular 3
basement membrane. These
include mutations affecting
the podocyte nucleus, 4
mito­chondria or lysosomes, the 2
slit diaphragm or actin
cytoskeleton, and the
Slit diaphragm 5
glomerular basement
membrane. Nephrin, podocin,
and CD2AP, for example, are
essential components of a
zipper-like structure spanning
the interdigitating foot Podocyte
processes of the podocyte, the effacement
slit diaphragm and link directly
with the podocyte actin
cytoskeleton. The actin
cytoskeleton is further Red White
supported by microfilaments Basement blood cell blood cell
6
membrane
that maintain structural
stability and facilitate the
dynamic nature of the podocyte
structure and function. The
importance of these Fenestrated
microfilaments is evident as endothelial
mutations in both α-actinin 4 cells
and INF2, which are involved in
actin regulation and
polymerisation lead to FSGS.

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 Seminar

podocyte has implications for the entire glomerular proteinuria, through an effect on either the glomerular
filtration barrier.22 basement membrane or the endothelial cells, and by
affecting the charge of the glomerular filtration barrier,
Immune mediated which prevents albumin from traversing the barrier. In
It is suspected that dysfunction or dysregulation of contrast, a sialylated form is released into circulation
T lymphocytes are involved in the pathogenesis of NS from other tissues and can mitigate proteinuria by
(figure 2).23–25 Supportive evidence includes the efficacy of binding αvβ5 integrins on the glomerular endothelium.
immunosuppressive agents in NS, spontaneous NS Exploration of how sialylated ANGPTL4 could be used to
remission following infection with measles,24 and the treat NS is ongoing, however, off-target effects, such
resolution of NS following chemotherapy for Hodgkin’s as inhibition of lipoprotein lipase leading to hyper­
and other T-cell lymphomas, which can trigger or precede triglyceridaemia in NS, could be exacerbated.32
NS.25 Lastly, development of NS after allergic reactions
to various stings and poisons suggests an immune- Genetics
mediated role in disease pathogenesis. Genetic risk and SSNS
A recent molecular candidate for the cause of A genetic locus on chromosome 6p and single
podocytopathies and proteinuric states is CD80 (B7-1). nucleotide polymorphisms in HLA-DQA1 and HLA-
CD80, is a protein expressed on antigen-presenting cells DQB1 were substantially associated with SSNS using an
that provides the primary co-stimulatory signal for T-cell exome array.36 This locus, however, only explains
activation via receptors on the T-cell surface. The T-cell 4∙6% of the genetic risk for SSNS.36 A common finding
surface expresses protein receptor CTLA-4, which binds from genome-wide association studies of glom­
CD80. An increase in podocyte B7-1 expression is erular diseases is the significant association with
evident in a variety of animal models of proteinuria and polymorphisms from the major histocompatibility
in human studies.26 This hypothesis was further tested complex. It is not clear whether the HLA loci are
through the CTLA-4 mimicking therapeutic agents, causal, given the commonality among glomerular
abatacept and belatacept in FSGS, but remains studies, or it reflects the allele frequency by specific
controversial and clinical trials are under way.27,28 ethnicity studied.36

Systemic circulating factors Genetics and SRNS

A circulating glomerular permeability factor has been Identifying genetic causes for children with SRNS early in
hypothesised to cause NS, however, defining a single their course could allow discontinuation of immuno­
putative factor remains elusive. The majority of studies suppressive agents, aid in transplant management, and
favour a circulating factor in SRNS or FSGS (figure 2). provide information for prenatal counselling. Con­
A few studies demonstrate proof of a blood-derived firmation of a genetic defect generally implies a reduced
glomerular permeability factor. For example, serum risk of recurrence afer transplantation, as it is likely
from patients with FSGS in pre-clinical and ex-vivo a kidney-specific disease. De novo auto-immune-mediated
studies induced proteinuria or increased permeability of NS can develop in the transplanted kidney owing to
glomeruli to albumin.29 There was also successful neoantigens,37 especially among children with NPHS1
treatment of recurrent FSGS after kidney transplantation (nephrin) mutations.38 Depending on the age of onset of
with immuno­adsorption. Finally, maternal transmission SRNS, the likelihood of defining a monogenic cause
of FSGS confirmed a circulating factor.30 There are num­ decreases as children age. Mutations in key podocyte
erous factors proposed including heparanase, haemo­ genes such as NPHS1, NPHS2, LAMB2, or WT1 explain
pexin, angiopoietin-like 4 (ANGPTL4), cardiotrophin-like 69–85% of cases of NS presenting in the first 3 months of
cytokine-1 and, more recently, soluble urokinase plasmino­ life and 50–66% of NS cases presenting between 4 and
gen activator receptor (suPAR).31–33 These factors might 12 months.39,40 After 1 year of age, the chance of identifying
impact glomerular permeability, possibly through effects a genetic cause for SRNS decreases substantially to
on the endothelial cell or podocyte. 25% between the ages of 1 and 6 years, 18% between 7 and
suPAR affects the podocyte actin cytoskeleton via an 12 years, and as low as 11% in those aged 13–18 years.39 In
interaction with αvβ3-integrin receptor on the surface of an international registry of over 1340 children with SRNS
podocytes. Increased suPAR con­ centrations were over 1 year of age, approximately 14% had a genetic
originally described in FSGS;34 however, suPAR as a mutation.41 Over 30 genes are reported to be associated
circulating factor has been refuted since concentrations with SRNS or FSGS, and the list is expected to expand
vary by kidney function, there is an absence of specificity (appendix). Mutations in the mitochondrial genes involved
for FSGS, and findings are not easily reproducible.35 in biosynthesis of coenzyme Q10 leading to deficiency,
Two distinct forms of ANGPTL4, a glycoprotein and occur in 1% of cases of familial SRNS.39 Coenzyme Q10 is
acute phase reactant expressed in adipose tissue, the an antioxidant and an essential component of the electron
heart, and skeletal muscle, are elevated in NS.32 A hypo­ chain and, most importantly, supplementation can be
sialylated form secreted from podocytes can lead to effective for mitochondrial podocytopathies—a potentially

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 Seminar

curative therapy. High-throughput next generation DNA is with low-molecular-weight heparin. There is in­
sequen­cing from patients with sporadic FSGS, targeting sufficient evidence to warrant universal thrombosis
all known podocyte genes, might identify other FSGS prophylaxis in childhood NS.50
susceptibility genes.42
Acute kidney injury (AKI)
Complications of nephrotic syndrome AKI, an underappreciated complication, is now rec­ognised
Infection as the third most important complication in children
Infection is the leading cause of morbidity and, treated in hospital with NS.53 Recently, a multicentre study
historically, mortality in children with NS.43 NS is from the USA reported that 58∙6% of 336 children
associated with low concentrations of immunoglobulin admitted to hospital for NS had evidence of AKI with
G (IgG) from urinary loss and altered production, which identified risk factors such as concomitant infections, use
contributes to infection risk. Loss of complement can of nephrotoxic medications and SRNS.53 The use of
also predispose to infection risk. Spontaneous bacterial diuretics in a child with haemoconcentration and intra­
peritonitis, especially by Streptococcus pneumoniae, vascular volume depletion might predispose to AKI. Renal
remains a serious complication of NS, and a low serum vein thrombosis, acute tubular necrosis in the setting of
albumin (<15 g/L or 1∙5 g/dL) is associated with hypovolaemia and sepsis, and interstitial nephritis in­
increased risk of peritonitis.44 Routine antibiotic duced by non-steroidal anti-inflammatory drugs or
prophylaxis for prevention of spontaneous bacterial antibiotics are also recognised contributors to AKI.
peritonitis in children with active NS is generally not
recommended owing to scarcity of evidence, although Dyslipidaemia
some centres could opt for prophylaxis in children with NS is associated with substantial abnormalities in lipid
a history of peritonitis.45 Pneumococcal vaccination can metabolism, leading to hypercholesterolaemia, hyper­
successfully be given to children with NS, even when triglyceridaemia, and various other lipoprotein abnor­
on steroid therapy, and is recommended by the malities. Lipid abnormalities are primarily related to
Children’s Nephrotic Syndrome Consensus Con­ urinary losses of key transport proteins including
ference.46,47 Children with NS are also at risk of albumin, which carries free cholesterol, and also a com­
developing pneumonia from Streptococcus pneumoniae, pen­satory increase in proteins involved in triglyceride
Haemophilus influenzae, Staphylococcus aureus, and metabolism.54 It is unknown whether altered lipid
cellulitis, caused by Staphylococci, group A Streptococci, metabolism confers long-term cardiovascular risk from
and H influenzae species.45 atherosclerosis in children with NS. The use of lipid-
Varicella-zoster infection poses a substantial risk to lowering agents for the dyslipidaemia in NS is not advised,
children with NS. The vaccine is a weakened form of unless there is substantial persistent proteinuria with
the virus, which is typically best avoided in immuno­ extremely high levels of hypertriglyceridaemia. The
compromised children. It appears to be safe, however, evidence of benefit is not clear and side-effects such as
for children who are in remission or who are on liver dysfunction, risk of rhabdomyolysis, and delayed
low-dose alternate-day steroids, an optimised, two-dose growth and development although rare are not in­
vaccination schedule has been developed.48 Prophylactic substantial.55 If statins are initiated, it is only recommended
varicella-zoster immune globulin (VZIG) is rec­ for children over the age of 10 years with monitoring of
ommended for exposure to chickenpox. VZIG should liver function and creatinine kinase prior to initiating
be given as soon as possible but can be given up to therapy and after 4 weeks.56
10 days after exposure. Therapeutic intravenous
aciclovir could also be effective in NS, however, data are Management
scarce and extrapolated from solid organ transplant­ Oedema in nephrotic syndrome
ation reports.49 Based on the pathogenesis of oedema in NS, one of the
primary strategies in the management of oedema is salt
Venous thromboembolism and fluid restriction with addition of a loop diuretic for
NS is a well recognised hypercoagulable state in severe or symptomatic oedema.57 The addition of an
which children are at risk of venous thrombo­ albumin infusion, typically in combination with a loop
embolism (VTE) including cerebral sinus venous throm­ diuretic, is sometimes employed to induce diuresis and
bosis, pulmonary embolism, and renal vein throm­bosis.50 natriuresis, especially if signs of intravascular underfilling
VTE complicates an estimated 3% of cases of NS during or severe oedema are present. Response to diuretics alone
childhood.50,51 The pathophysiology of VTE in NS is multi­ might be blunted, especially in an underfilled state, where
factorial resulting from abnormalities in platelet aggre­ there is activation of neurohormonal systems in an attempt
gation, increased synthesis of prothrombotic factors to maintain intravascular volume. Furthermore, furo­
(factors V and VIII), urinary loss of anticoagulant semide is highly protein bound and, in a hypoalbuminaemic
proteins (antithrombin III, protein C and S), altered state, the volume of distribution substantially increases
fibrinolysis, and intra­vascular fluid depletion.52 Treatment with less drug available to reach the proximal tubule for

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 Seminar

secretion into the urinary space. The combined use of

FRNS
albumin and furosemide remains controversial. Many or SDNS Low dose
studies involved small numbers of patients, were largely alternate day
steroids
uncontrolled, and, in most, only a small benefit of diuresis, SSNS
Ongoing relapses
Infrequent
natriuresis, and weight loss were observed with the relapses or steroid toxicity
combination of furosemide and albumin over furosemide Cyclophosphamide
alone. Approximately 25% of children with NS might or levamisole
actually be hypovolaemic at presentation, as assessed by Long-term
Ongoing relapses
Steroids or steroid toxicity
clinical, laboratory, and echocardiographic parameters.58 remission
Biopsy every
Diuretics alone might aggravate hypovolaemia and 2–3 years Tacrolimus or
mycophenolate mofetil
intravascular depletion, thus, the use of albumin could be
warranted. Care should be taken with the administration No response after Ongoing relapses
8 weeks of steroids Biopsy every or steroid toxicity
of albumin in children who are not exhibiting signs of 2–3 years
SRNS Rituximab ± other
hypovolaemia, as the resultant expansion in intravascular
immunosuppressants
fluid could precipitate pulmonary oedema.57
Tacrolimus

Management of nephrotic syndrome Genetic cause

No response

Standardising management of NS has been hampered confirmed ACE inhibitor

ARB
by the paucity of high-quality trial evidence supporting
international guidelines. This lack of evidence has
Progression over time to ESRD
resulted in substantial variation in care based on
physicians’ preference, drug availability by country, and Figure 3: Principal treatments for nephrotic syndrome at diagnosis and follow-up
interpretation of the sparse trial data. Substantial After initial therapy with steroids, children are classified as having SSNS or SRNS after at least 8 weeks of therapy.
physician variability in choice of steroid-sparing agents Frequently relapsing SSNS can first be treated with low-dose alternate-day steroids prior to consideration of
steroid-sparing agents. Typically, the steroid-sparing agents include cyclophosphamide, or levamisole, and if this fails
for children with NS is described in Europe, Canada, and the child continues to relapse or is steroid dependent, then a calcineurin inhibitor is often the next agent, or
and the USA.59,60 In the following section, we outline the mycophenolate mofetil. The scarcity of trial evidence has resulted in substantial variation in choice of steroid-sparing
principal treatments for NS (figure 3). Certain agents, agents based on physicians’ preference, drug availability by country, and cost. SSNS=steroid sensitive nephrotic
such as mizoribine, or chlorambucil with restricted syndrome. SRNS=steroid resistant nephrotic syndrome. FRNS=frequently relapsing nephrotic syndrome.
SDNS=steroid dependent nephrotic syndrome. ACE=angiotensin converting enzyme inhibitor. ARB=angiotensin
availability are not discussed in detail.1 Baseline and receptor blocker.
additional investigations, as well as considerations
for genetic testing and renal biopsy are presented and require steroids into adulthood, osteo­ porosis and
in panel 3. being overweight cause substantial morbidity.9

Initial therapy Treatment of frequently relapsing nephrotic syndrome

Standard therapy is at least 4–6 weeks of steroids each (FRNS) or steroid-dependent nephrotic syndrome
day (prednisone or prednisolone), followed by a mini­ (SDNS)
mum of 6 weeks of alternate day therapy based on For relapses of SSNS, the efficacy of steroids is not in
evidence from clinical trials.1 Many published protocols doubt; however, tapering schedules remains controversial,
by guideline, centre, or country highlight the variability as data are scarce.1,64 KDIGO recommends a tailored
in the prednisone taper (table). approach to steroid therapy depending on whether
Until recently, a Cochrane review strongly suggested that children relapse either infrequently or frequently (table).1
6 months of therapy was superior to 2–3 months, owing to
a substantial reduction in relapses after initial presentation Triggers of relapse
of NS. The meta-analysis of randomised controlled trials Additional factors triggering relapses include allergies and
(RCTs) involved over 700 children.64 Since 2013, three RCTs infection. Treatment for allergies with dietary restrictions,
demonstrated that extending treatment to 6 months skin desensitisation, mast cell stabilisers such as disodium
compared with 2–3 months did not reduce the risk cromoglycate demonstrate little benefit in preventing
of relapse, the development of frequent relapses, or relapsing disease.69 On the contrary, several trials suggest
steroid dependence and the eventual need for an add- that relapses might be reduced if prednisolone is
itional immunosuppressive agent.65–67 Thus, treatment administered daily for 5–7 days at the onset of upper
with steroids for 6 months is no longer recommended.68 respiratory tract infection in FRNS or SDNS. Although
Chronic steroid use is associated with many side-effects studies have a high risk of bias owing to small sample
including obesity, cushingoid features, striae, ocular sizes and variability in study design, treatment is still
complications, such as cataracts and glaucoma, metabolic recommended by the KDIGO guide­ lines.1,70–72 A large,
features, musculoskeletal features, such as osteoporosis placebo-controlled, multicentre trial of 300 children in the
and avascular necrosis of the head of the femur, and UK (PREDNOS 2) will clarify the effectiveness and safety
behavioural features. In those that continue to relapse of this approach when completed.73

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International Arbeitsgemeinschaft Haute Autorité de Santé Italian Society for KDIGO Glomerulonephritis Hospital for Sick Children
Study of Kidney für Pädiatrische (France)62 Pediatric Nephrology Guidelines1 (Toronto, Canada)11
Disease in Children Nephrologie (APN)2 (SINePe)63
(ISKDC)61
Year of 1970 1988 2008 2017 2012 2016
publication
Initial presentation
Initial dose 60 mg/m² per 60 mg/m² per 60 mg/m² per day × 4 weeks 60 mg/m² per 60 mg/m² per day or 2 mg/kg 60 mg/m² per day × 6 weeks
and day × 4 weeks day × 6 weeks (maximUm (maximum dose 60 mg) day × 6 weeks per day × 4–6 weeks (maximum (maximum 60 mg in single
duration dose 80 mg) (maximum 60 mg in 60 mg) morning dose)
single or 2 divided
doses)
Subsequent 4 weeks of 40 mg/m² per 60 mg/m² per alternate 40 mg/m² per 40 mg/m² per alternate day or 40 mg/m² per alternate
dose and 40 mg/m² alternate day × 6 weeks day × 8 weeks (maximum 60 mg) alternate day × 6 weeks 1∙5 mg/kg/alternate day day × 6 weeks
tapering per alternate day but (maximum dose 60 mg) followed by a 15 mg/m² per (single dose; maximum (maximum 40 mg ) × 6–8 weeks (maximum 60 mg), 30 mg/m²
given on alternate day × 15 days and 40 mg) without (at least 12 weeks) and per alternate day × 8 days
3 consecutive days continue to wean. In addition, tapering continued for 2–5 months with (maximum 30 mg), 20 mg/m²
out of a week 3 methylprednisolone pulses if tapering per alternate day × 8 days
proteinuria persists after 1 month (maximum 20 mg), 10 mg/m²
of daily prednisone therapy per alternate day × 12 days
(maximum 10 mg)
Relapses
Starting ·· ·· 60 mg/m² per day until urine 60 mg/m² (max 60 mg 60 mg/m² per day or 2∙0 mg/kg 60 mg/m² per day until urinary
dose and protein is negative for 6 days in a single or 2 divided per day (maximum of protein is trace or negative for
duration doses) until urine 60 mg/day) until urine is 5 consecutive days
protein is negative for negative for 3 days
5 days
Follow-up ·· ·· 60 mg/m² per alternate 40 mg/m² per 40 mg/m² or 1∙5 mg/kg/ 60 mg/m² per alternate
dose and day × 4 weeks, 45 mg/m² per alternate day (max alternate day (maximum day × 8 days (maximum
duration alternate day × 4 weeks, 40 mg) × 4 weeks 40 mg) × 4 weeks (minimum) 60 mg/day), 50 mg/m² per
30 mg/m² per alternate alternate day × 8 days
day × 4 weeks, 15 mg/m² per (maximum 50 mg/day),
alternate day × 4 weeks 40 mg/m² per alternate
day × 8 days (maximum
40 mg/day), 30 mg/m² per
alternate day × 8 days
(maximum 30 mg/day),
20 mg/m2/alternate
day × 8 days (maximum
20 mg/day), 10 mg/m2 per
alternate day × 8 days
(maximum 10 mg/day)
Frequent ·· ·· ·· ·· 60 mg/m2 per day or ··
relapses 2∙0 mg/kg per day (maximum of
60 mg/day) until urine is
negative for 3 days followed by
alternate-day prednisone for at
least 3 months; use the lowest
dose to maintain remission
without major adverse effects
and daily if alternate day is
ineffective

Table: Published protocols for steroid treatment (prednisone or prednisolone) for initial presentation of idiopathic nephrotic syndrome

Low-dose, alternate-day steroid medications and physician preferences greatly influence

In general, the first step in managing a child with choice of steroid-sparing medication (panel 4).59,60 We
frequent relapses is to maintain them on low-dose, provide the list of agents below based on the strength of
alternate-day steroid, typically at the lowest dose possible, evidence (figure 3).
or just above the steroid dose associated with the latest
relapse. Children could be treated with steroid-sparing Steroid-sparing agents
agents when low-dose alternative-day steroid therapy Levamisole, an antihelminthic agent, has immuno­
fails or when severe adverse effects of steroids develop modulatory properties and a favourable side-effect profile.
(figure 3). The decision to choose steroid-sparing treat­ Levamisole reduced the risk of relapse compared with
ments should be based on drug efficacy, side-effects and placebo or no treatment.74,75 There was, however, con­
the patient’s condition. Also, regional availability of siderable heterogeneity in study design described in a

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meta-analysis.76 An international, multicentre, double-

blind, placebo-controlled, RCT of levamisole in SSNS Panel 4: Steroid-sparing agents for frequently relapsing
found that 26% of patients on placebo versus 6% on nephrotic syndrome (FRNS) or steroid-dependent
levamisole were in remission at 1 year.103 nephrotic syndrome (SDNS)
Cyclophosphamide, the most commonly used steroid- Levamisole
sparing agent, is effective in multiple RCTs for the • Reduces risk of relapse compared with placebo or no
treatment of FRNS and SDNS.78–81 A Cochrane review treatment;74,75 there was, however, considerable
reported that cyclophosphamide substantially reduced heterogeneity in the meta-analysis76
the relapse risk at 6–12 months by 56% when compared
to prednisolone alone (relative risk [RR]] 0∙44, 95% CI Cyclophosphamide
0∙26–0∙73).76 A meta-analysis reported that studies for • Effective for FRNS,76,77,79 but less so for steroid-dependent
non-steroid-dependent FRNS resulted in remission in nephrotic99 syndrome;43,79–81,82 however, there is overlap in
72% of patients after 2 years and 36% after 5 years, the classification
whereas the proportions for SDNS were 40% and 24%, Ciclosporin
respectively.43 Studies to date used various definitions • Effective for FRNS or SDNS,83–90 but many patients suffer
of response, which leads to hetereogeneity in re­ relapses after discontinuation of ciclosporin therapy
ported outcomes. (ciclosporin dependence)85,86,89–91
Important side-effects of cyclophosphamide include
gonadal dysfunction (azoospermia in boys), myelo­ Tacrolimus
suppression (leucopenia), infection, alopecia, haemor­ • Several case series suggest that tacrolimus is effective for
rhagic cystitis, and hepatic dysfunction. Meta-analyses FRNS or SDNS,92–96 but there are no randomised controlled
report that risk of azoospermia is higher in boys of trials
pubertal age (Tanner stage 2 or greater) or post-pubertal Mycophenolate mofetil
age, especially when the cumulative dose of cyclo­ • Less effective than ciclosporin,97,98 but has a favourable
phosphamide ranges from 100 to 300 mg/kg, but higher side-effect profile
doses could be safe in pre-pubertal boys.43,104 In NS,
substantially lower doses of cyclophosphamide are Rituximab
prescribed typically, 2–2∙5 mg/kg on average for • Rituximab and lower doses of prednisone and calcineurin
8–12 weeks, with a maximum daily dose of 100 mg and inhibitors are non-inferior to standard doses of these
only as a single course.1 The risk of female infertility is agents in maintaining short-term remission in children
documented to be lower than in boys, and a cumulative who show dependence on both drugs, and allow their
dose up to 200 mg/kg is reported safe105 as infertility temporary withdrawal99
occurred at a dose of 300 mg/kg or higher.104 Approxi­ • Effective for complicated FRNS or SDNS, but all children
mately 32% of NS patients developed leucopenia, during had relapses by 19 months after rituximab infusion100
cyclophosphamide therapy.43 Therefore, if the leucocyte • Non-inferior to steroids in maintaining remission in SDNS101
count drops below 4500 cells per μL, a lower dose could be Mizoribine
used or suspended if the leucocyte count falls below • Not effective for SDNS, but a subgroup analysis of
3000 cells per μL.43 Long-term studies with decades of children aged 10 years and younger demonstrated that
follow-up are needed to understand long-term risk of the proportion of patients who relapsed was substantially
cyclophosphamide. lower in the mizoribine group than the placebo group102

Calcineurin inhibitors
Ciclosporin is effective for both FRNS and SDNS.83–87 increasing risk after prolonged use of the drug for 2 years
Blood concentration of ciclosporin should be monitored, or more.106,107
usually by trough levels or C2 (at 2 h post-dose) levels, Tacrolimus could be considered when ciclosporin
and the dose should be adjusted within target cannot be used owing to cosmetic side-effects, including
levels (trough levels: 60–100 ng/mL; C2 levels: hypertrichosis and gingival hypertrophy. Both medi­
300–700 ng/mL).83,84,88 There is, however, no international cations are now generic, thus cost should not be an issue.
consensus on target con­ centrations owing to incon­ Potential onset of diabetes and nephrotoxicity are
clusive evidence.1 In Japan, dose is adjusted to maintain important side-effects. No definitive dosing for tacro­
trough concentrations within 80–100 ng/mL for the first limus is established, but it typically starts at 0∙1 mg/kg
6 months, and within 60–80 ng/mL for the next per day (range 0∙05–0∙2).97,98,108 Optimal trough con­
18 months, and in North America, reported levels range centrations are not defined but ranges from 5 to 8 ng/mL
from 50 to 100 ng/ml.85,86,91 Additionally, the length of have been reported, and persistent levels greater
therapy is not well defined as children frequently than 8 ng/mL were associated with increased risk of
relapse after discontinuation of the drug (ciclosporin nephrotoxicity in a single study.93,94 Hypertension could
dependence).85,86,91 Nephrotoxicity is also problematic with also be worsened with calcineurin inhibitors and

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could potentiate the development of posterior reversible Rituximab is generally safe and well tolerated in most
encephalopathy syndrome.108 children; however, potentially serious adverse events
include persistent low B cell and failure to repopulate,
Mycophenolate mofetil (MMF) depletion of memory B cells , and a risk of hypo­
Mycophenolate mofetil (MMF) is used as a steroid- gammaglobulinaemia, occasionally requiring infusions
sparing agent for FRNS or SDNS owing to the favourable of immunoglobulin. Rarer adverse events are also report­
side-effect profile and absence of nephrotoxicity. ed, including fatal hepatitis induced by reactivation
Physician preference for MMF stems from the concerns of hepatitis B virus, progressive multifocal leuko­
about the toxicity of cyclophosphamide and calcineurin encephalopathy, pulmonary fibrosis, fulminant myo­
inhibitors; however, trial evidence is scarce. A randomised, carditis,111 pneumocystis pneumonia,112 immune-mediated
multi­centre, open-label, crossover study comparing the ulcerative colitis, and agranulocytosis. Recently, hyper­
efficacy and safety of a 1-year treatment with MMF or sensitivity reactions were reported with autoantibodies to
ciclosporin in 60 pediatric patients with FRNS, reported rituximab during the second course of rituximab.113
more relapses per patient per year with MMF than with Despite the benefit of rituximab, residual issues require
ciclosporin.96 Similar results were reported in another further study such as the total number of infusions,
multicentre RCT comparing the efficacy of MMF to that whether to redose every 6 months or base dose on
of ciclosporin in 24 children with FRNS and biopsy- repopulation of CD20 B cells. Importantly, we need to
proven MCD.98 A French study that employed Bayesian understand the long-term consequences of rituximab
techniques and probability in 23 children, found that therapy in children as treatment is considered earlier in
MMF could reduce the number of relapses and steroid disease course.
doses, suggesting use of MMF prior to cyclophosphamide
or ciclosporin.109 Recent studies demonstrate efficacy at Treatment for steroid-resistant nephrotic syndr ome
higher doses, which are not routinely monitored and Identification of a podocyte gene defect is fundamental to
typically used in kidney transplant­ation. Maintaining an determining treatment response to steroids and calci­
area under the curve for myco­phenolic acid, assessed by neurin inhibitors as demonstrated in recent studies.114,115
pharmacokinetic studies higher than 45 mg × h per L, SRNS with no proven genetic mutation is expected to
might be associated with less frequent relapses.110 respond with complete remission in up to 60% of cases
and with partial remission in up to 19%.114,115 Furthermore,
Rituximab those with no genetic mutation have a substantial
Rituximab, a chimeric anti-CD20 monoclonal antibody, advantage in terms of kidney survival over 10 years, with
is effective and allows for discontinuation or reduction ESRD occurring in 71% of those with a genetic disease
of steroids and other steroid-sparing agents in NS. An versus 29% in those without.114
initial open-label RCT concluded that rituximab and Calcineurin inhibitors such as ciclosporin and tacro­
lower doses of prednisone and calcineurin inhibitors are limus are recommended as initial therapy for children
non-inferior to standard therapy in maintaining short- with SRNS,1,116 with cumulative complete and partial
term re­mission.99 Findings were confirmed by a multi­ remission in ciclosporin treatment substantially better
centre, double-blind, randomised, placebo-controlled than placebo.117–119 Also, tacrolimus is similar to ciclosporin
trial that assessed efficacy and safety of rituximab versus in combination with low-dose steroids in inducing
placebo in 48 children with complicated FRNS or remission in patients with SRNS.120 Optimal duration of
SDNS.100 Those on rituximab received 375 mg/m² body calcineurin inhibitor therapy is still unknown, although
surface area (maximum 500 mg) once weekly for KDIGO guidelines recommended a minimum of
4 weeks, and the placebo group received placebo at 12 months,1 and in clinical practice, can be con­
similar frequency. Prednisolone was gradually tapered tinued up to 24 months. Combination therapy in­
after remission was achieved. Tapering of ciclosporin volving steroid pulse therapy and ciclosporin could be
was started on day 85, and discontinued by day 169. The considered effective in inducing remission of SRNS in
50% relapse-free period (267 vs 101 days; hazard ratio extreme cases.121,122
[HR] 0∙267, 95% CI 0∙135–0∙528, p<0∙0001), and the Two RCTs demonstrated a substantial reduction in
daily steroid dose was substantially lower in those on proteinuria with enalapril123 and fosinopril.105 KDIGO
rituximab than placebo (9∙12 [SD 5∙88] vs 20∙85 therefore recommended angiotensin-converting enzyme
[SD 9∙28] mg/m² per day, p<0∙0001) up to 1 year. In inhibitors or angiotensin II receptor blockers for children
follow-up, all children relapsed by 19 months, suggesting with SRNS.1
that the benefit of rituximab was not permanent. Re­ Cyclophosphamide has no benefit for SRNS.78,124 MMF
cently, rituximab was also shown to be non-inferior to use in the treatment of SRNS has been described and the
steroids in maintaining remission in patients with proportion of patients in remission is low.125–127 A recent
SDNS never exposed to a calcineurin inhibitor and who randomised trial of 138 children evaluated dexamethasone
had not received either MMF or cyclophosphamide in plus MMF as a therapy for patients with steroid-resistant
the preceding 6 months.101 FSGS versus ciclosporin, and found no significant

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writing of the manuscript, and construction of the figures, panels, and

difference in achieving partial or complete remission tables. All authors reviewed and approved the final version.
at 1 year; however, the trial was substantially under­ Declaration of interests
powered.128 Several case series suggested that rituximab is DGN declares no competing interests. KI has received grants from
effective with refractory (failing to respond to calcineurin Novartis Pharma, Japan Blood Product Organization, AbbVie,
JCR Pharmaceuticals, Daiichi Sankyo, Teijin Pharma, CSL Behring, Novo
inhibitors) SRNS; however, an open-label, randomised Nordisk Pharma, Air Water Medical, Astellas Pharma, Takeda
trial of rituximab failed to demonstrate an improvement Pharmaceutical, Taisho Toyama Pharmaceutical, Eisai, and Biofermin
in 31 children with SRNS, compared to either 16 children Pharmaceutical, and lecture fees or consulting fees, or both from Zenyaku
who received calcineurin inhibitors, prednisolone, and Kogyo, Novartis Pharma, Chugai Pharmaceutical, Astellas Pharma,
Springer Japan, Meiji Seika Pharma, Asahi kasei Pharma Corporation,
two infusions of rituximab, or 15 children who received Medical Review, Nippon Boehringer Ingelheim, Baxter Limited, Ono
calcineurin inhibitors and prednisolone alone.129 Pharmaceutical, Sanwa Kagaku Kenkyusho, Sanofi, Alexion Pharma, and
Kyowa Hakko Kirin. RP has received grants from Astellas Pharma.
Controversies, uncertainties, and outstanding References
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