2018 Lancet nefroìtico

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
region. The cause remains unknown but the pathogenesis of idiopathic NS is thought to involve immune
dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. Genetic risk is more
commonly described among children with steroid-resistant disease. The mainstay of therapy is prednisone for the
vast majority of patients who are steroid responsive; however, the disease can run a frequently relapsing course,
necessitating the need for alternative immunosuppressive agents. Infection and venous thromboembolism are the
main complications of NS with also increased risk of acute kidney injury. Prognosis in terms of long-term kidney
outcome overall is excellent for steroid-responsive disease, and steroid resistance is an important determinant of
future risk of chronic or end-stage kidney disease.
Introduction
Nephrotic syndrome (NS) is characterised by the triad of
proteinuria, hypoalbuminaemia, and oedema (panel 1).
Many glomerular disorders in childhood present with
nephrotic syndrome, however, the vast majority are
idiopathic NS, and the focus of this Seminar (panel 2).
The precise cause of this common childhood disease
remains elusive despite substantial advances in our
understanding of podocyte biology. Idiopathic NS can
be classified on the basis of response to steroid therapy,
pattern of relapse, histopathology, or by genetic
mutations. Most simply, NS is categorised on the basis
of clinical response to steroid therapy, as steroid
sensitive (SS) or steroid resistant (SR). Although helpful
for guiding therapy, this classification lends very little
understanding to disease mechanism. Idiopathic NS
is best defined as a podocytopathy due to loss or
altered function of the podocytes, resulting in massive
proteinuria.
The mainstay of treatment for NS is corticosteroids
(steroids) with protocols largely based on seminal studies
from the International Study of Kidney Disease in
Children and the Arbeitsgemeinschaft für Pädiatrische
Nephrologie.2,3 Steroid responsiveness and frequency
of relapses provide the best guide to therapy in
idiopathic NS. The majority of children respond well to
steroids within 4 weeks (steroid-sensitive NS [SSNS]);
however, most will relapse, with approximately half
becoming frequent relapsers or steroid dependent.4,5
Although historically fewer than 10% of children
with SSNS continue to have relapses in adulthood,3,6
contemporary cohorts suggest higher proportions of
16∙4–42%. Frequency of relapses during childhood and
the need for non-steroid immuno­suppressants such as
cyclophosphamide or ciclosporin are predictive of active
disease as young adults.7–-10 Among 287 children followed
up for over 15 years, 85% achieved long-term remission.11
Despite ongoing relapses, kidney outcomes remain
excellent, with risk of progression to chronic kidney
disease estimated to be less than 5% in those with SSNS
at 10 years after diagnosis.12 In contrast, SRNS is
associated with increased risk of progression to end-stage
renal disease (ESRD).13 Children with SRNS on biopsy
www.thelancet.com Vol 392 July 7, 2018
might have minimal change or focal segmental
glomerulosclerosis (FSGS). Owing to the heterogeneity of
SRNS, only 50% are at risk of progressing to ESRD in
5 years; typically those children who do not achieve
complete or partial remission.14 Long-term prognosis in
adults with paediatric onset NS is not well studied and
would provide important information on risk for families.
Standard definitions are established and highlighted in
the 2012 Kidney Disease Initiatives: Global Outcomes
(KDIGO; panel 1).1
Clinical presentation
Classically, a child presents with a history of progressive
oedema, initially periorbital and noticeable in the
morning. There can be an antecedent infection, typically
of the upper respiratory tract. Urine output is described
as frothy or foamy. Abdominal pain is relatively common
and, if accompanied by fever, could signify spontaneous
bacterial peritonitis. Headache with accompanying
neurological signs or irritability should raise the
suspicion for cerebral venous sinus thrombosis. Clinical
investigations are summarised in panel 3.
Lancet 2018; 392: 61–74
Published Online
June 14, 2018
http://dx.doi.org/10.1016/
S0140-6736(18)30536-1
This online publication has been
corrected. The corrected version
first appeared at thelancet.com
on July 26, 2018
Department of Paediatrics,
University of Toronto, Toronto,
ON, Canada
(D G Noone MB BCh BAO,
Prof R Parekh MD); Division of
Nephrology, The Hospital for
Sick Children, Toronto, ON,
Canada (D G Noone,
Prof R Parekh); Department of
Pediatrics, Kobe University
Graduate School of Medicine,
Kobe, Japan (K Iijima MD); Child
Health Evaluative Sciences,
Research Institute, Hospital for
Sick Children, Toronto, ON,
Canada (Prof R Parekh);
University Health Network,
Toronto, ON, Canada
(Prof R Parekh); and Dalla Lana
School of Public Health, and
Health Policy, Management
and Evaluation, University of
Toronto, Toronto, ON, Canada
(R Parekh)
Correspondence to:
Dr Rulan Parekh, The Hospital for
Sick Children, Toronto,
ON M5G 1X8, Canada
[email protected]
Pathology
Most children do not get a kidney biopsy at presentation.
Historical studies have demonstrated that the most
Search strategy and selection criteria
We conducted a systematic literature search of published
literature using Cochrane, PubMed, Embase, and MEDLINE.
Key search terms included “children”, “nephrotic
syndrome”, “steroid sensitive nephrotic syndrome”, “steroid
resistant nephrotic syndrome” and “focal segmental
glomerulosclerosis”. The reference lists of all included
papers and review articles were also cross-referenced to
identify additional relevant studies. The search was not
limited by study design, year of publication, or language
but precedence was given where possible to randomised
controlled trials and studies from the last 5 years. The initial
search was done on Nov 29, 2015 and repeated on Dec 1,
2017 to update with the recent published clinical trials.
61
Seminar
Panel 1: Relevant definitions in nephrotic syndrome1
Nephrotic syndrome (NS)
Oedema with protein excretion >40 mg/m² per h or urine
protein:creatinine ratio ≥2000 mg/g (≥200 mg/mmol) or
>3+ proteinuria on dipstick with serum albumin <2∙5 g/dL
(25 g/L)
Remission
Urine albumin trace or negative on dipstick or proteinuria
<4 mg/m² per h or urinary protein:creatinine ratio <200 mg/g
(20 mg/mmol) for 3 consecutive days
Panel 2: Causes of non-idiopathic childhood nephrotic
syndrome (NS)
• Nephritic/nephrotic glomerular disorders
• IgA nephropathy and Henoch–Schonlein purpura
• Membranoproliferative glomerulonephritis
• Lupus nephritis
• Postinfectious glomerulonephritis
• Immune complex mediated glomerulopathy
• C1q nephropathy
• Thin basement membrane disease
Relapse
Urine albumin 3+ or 4+ or proteinuria >40 mg/m² per h or
urinary protein:creatinine ratio >200 mg/g (20 mg/mmol) for
3 consecutive days
• Membranous nephropathy
Frequently relapsing NS
≥2 relapses within 6 months of initial response or ≥4 in any
12 month period
• Interstitial nephritis
Steroid-dependent NS
2 consecutive relapses occurring while weaning to alternate
day steroids or within 2 weeks of steroid discontinuation
Steroid-resistant NS
Persistent proteinuria despite 60 mg/m² or 2 mg/kg for
8 weeks, after ensuring no infection or non-adherence to
medication
common pathological findings in childhood NS are
either classified as minimal change and termed
minimal change disease (MCD) or FSGS.1 In minimal
change, the glomeruli appear normal under light
microscopy, with evidence of podocyte effacement by
electron microscopy.17 Characteristic histology in FSGS
is segmental sclerosis of affected glomeruli, with the
segment often adherent to Bowman’s capsule by
synechiae.18
• Sickle-cell nephropathy
• Thrombotic microangiopathy
• Infections associated with NS
• Hepatitis B and C
• HIV-1
• Malaria
• Syphilis
• Toxoplasmosis
• Varicella zoster
• Drugs associated with NS
• Non-steroidal anti-inflammatory drugs
• Bisphosphonates
• d-penicillamine
• Heavy metals (mercury and gold)
• Lithium
• Rifampicin
• Sulfasalazine
• T-cell-related malignancy
• Hodgkin’s lymphoma
• Thymoma
• Leukaemia
Incidence
There is considerable variation in incidence of NS
depending on country of origin, or ethnicity, with
proportions ranging from 1∙15 to 16∙9 per
100 000 children (figure 1).11,19 Incidence is highest in
those of south Asian ancestry compared to European
ancestry as reported in studies from the UK,
South Africa, and Canada. Incidence of steroidresistance ranges from 2∙1 to 27∙3% and also varies by
country of origin (figure 1).19 Most studies are
retrospective or cross-sectional with only a few
longitudinal studies. Reported differences can thus be
partially attributable to management variations across
practices or regions, as well as use of differing
definitions of outcomes. African–American children
are more likely to have biopsy-proven FSGS (42–72%)19
and have the highest proportion of progression to
ESRD as compared to European Americans,20 whereas
62
in south Asian children, FSGS is reported less
commonly and ranges from 15 to 39%.19
Pathophysiology
Abnormalities in the podocyte and glomerular filtration
barrier
The podocyte is a polarised epithelial cell with inter­
digitating foot processes with a unique cell–cell junction
known as the slit diaphragm. Along with the glomerular
basement membrane and the fenestrated glomerular
endothelium, the podocyte forms a trilayered structure—
the glomerular filtration barrier. The podocyte and
filtration barrier allow an ultrafiltrate almost completely
devoid of protein to pass into the Bowman’s space and
proceed onto the proximal tubule. Podocyte architecture
is maintained by an extensive actin cyto­
skeleton that
enables the glomerular filtration barrier to withstand the
www.thelancet.com Vol 392 July 7, 2018
Seminar
Panel 3: Investigations in a child with nephrotic syndrome
(NS)
Baseline investigations
1 Urinalysis and urine microscopy
2 Urine albumin or protein:creatinine ratio
3 24-h timed collection of urine for protein quantification
4 Serum electrolytes, albumin, total protein, renal function,
and cholesterol
A
substantial capillary hydrostatic pressure. Loss of normal
podocyte structure, the foot processes or the slit
diaphragm that spans these interdigitations can lead to
loss of albumin in the ultrafiltrate. Podocytes are
terminally differentiated cells with minimal regeneration
and thus, vulnerable to injury.
Complete effacement of the podocyte with the loss of
normal architecture results in massive proteinuria, a
hallmark of nephrotic syndrome (figure 2). The
pathogenesis leading to podocyte effacement is not clear
in idiopathic NS, nor the specific mechanism in
which treatment with steroids leads to the recovery of
podocyte structure and function. Systemic factors,
immune mediated or circulating, can contribute to
podocyte effacement, but there is no single uni­
fying hypo­
thesis. Supporting evidence from rare or
www.thelancet.com Vol 392 July 7, 2018
Multi-ethnic (n= 49)*
Australia
Not specified (n=135)
The Netherlands
Not specified (n=231)
Kentucky, USA
Not specified (n=34)
Benghazi, Libya
Arabs (n=134)
Arabs (n=55)
Ohio, USA
African-Americans (n=15)
Whites (n=157)
Kansas City, USA
African-Americans (n=25)
Europeans (n=54)
Erie county, USA
Whites (n=9)
Non-whites (n=73)
Birmingham, UK
Afro-Caribbeans (n=2)
Europeans (n=15)
Asians (n=27)
Former Yorkshire, UK
Non-Asians (n=49)†
Asians (n=121)†
Leicestershire, UK
Non-Asians (n=22)
Asians (n=21)
Toronto, Canada
East/Southeast Asians (n=69)
South Asians (n=237)
Europeans (n=173)
Others (n= 232)
Infectious work-up depending on clinical context
1 Hepatitis B and C, HIV, syphilis, or tuberculosis can also be
considered depending on the clinical context
Renal biopsy considered in the following situations
1 Age <1 or >12 years
2 Persistent or sustained elevation in creatinine
3 Significant haematuria or gross haematuria16
4 Hypocomplementaemia
5 Findings indicative of another autoimmune disease
6 Infection with hepatitis B or C, HIV, or tuberculosis
7 Hypertension
8 Glucocorticoid resistance
Ethnicity (n)
New Zealand
Farwaniya/Jahra, Kuwait
Additional testing if there is a suspicion of a
glomerulonephritis
1 Serum complement C3 and C4 concentrations
2 Serum immunoglobulins
3 Antistreptolysin titres
4 Anti-DNAse B antibodies
5 Antinuclear antigen antibodies
6 Anti-double-stranded DNA antibodies
7 Anti-neutrophil cytoplasmic antibodies
Consideration of genetic testing
1 A positive family history of NS
2 Congenital NS
3 Infantile onset (<1 year)
4 Failure to respond to steroid therapy
5 Persistent kidney dysfunction
6 Features suggestive of a known syndrome (appendix)15
City, country
0
2
4
6
8
10
12
14
16
18
Incidence‡ (per 100 000 people)
B
Steroid resistant
City, country
Ethnicity (total n, SR%)§
New Zealand
Multi-ethnic (n=49, 19·6%)
Steroid sensitive
Durban, South Africa Black and Indian (n=816, 27·3%)
Diyarbakir, Turkey
Turkish (n=138, 13·2%)
Sindh, Pakistan
Pakistani (n=538, 31·1%)
Siem Reap, Cambodia
Cambodian (n=112, 6·2%)
Poland
Boston and New York,
USA
Polish (n=178, 24·7%)
European (n=65, 6·2%)
Black and Hispanic
(n=177, 15·3%)
New Orleans, USA African-American (n=96, 11·0%)
Caucasian (n=103, 3·6%)
Toronto, Canada
Others (n=232, 2·6%)
East/Southeast Asians
(n=66, 4·5%)
South Asians (n=237, 2·1%)
Europeans (n=173, 6·8%)
0
10
20
30
40
50
60
70
80
90 100
%
Figure 1: Incidence of childhood nephrotic syndrome per 100 000 persons by ethnicity, reported from
1946 to 2014 (A) and variability of steroid responsiveness by ethnicity among children with nephrotic
syndrome in reported studies from 1986 to 2014 (B)
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,
Maori, Pacific Island, Asian, Other. †Only those with steroid-sensitive nephrotic syndrome. ‡Estimated on the basis
of data in published studies.
familial forms of nephrotic syndrome underscores
the importance of genetic variants leading to specific
podocyte abnormalities.
63
Seminar
Congenital and steroid-resistant forms of NS are
associated with mutations in genes encoding com­
ponents of the slit diaphragm, podocyte actin cyto­
skeleton, podocyte mitochondrial proteins, lysosomal
proteins, nuclear transcription factors, and glomerular
basement membrane (figure 2).21 Maintenance of
Figure 2: The glomerular
filtration barrier and
pathogenesis of idiopathic
nephrotic syndrome
Within the kidney is the
glomerulus, a capillary tuft that
filters the blood. The podocyte,
glomerular basement
membrane and the fenestrated
glomerular endothelium
comprise the glomerular
filtration barrier allowing the
ultrafiltrate to enter the urinary
space. The podocyte has
extensive cellular extensions
that interdigitate and these
foot processes are connected by
the slit diaphragm. In nephrotic
syndrome, there is extensive
effacement of the podocytes
and loss of this barrier to
protein, allowing excessive
serum albumin to leak into the
urine. The pathogenesis of
idiopathic nephrotic syndrome
is hypothesised to be either
immune-mediated, owing to a
systemic podocyte-derived
circulating factor, or, in rarer or
familial forms, a genetic variant.
Numerous mutations are
associated with steroidresistant nephrotic syndrome
that affect various parts of the
podocyte itself, or the other
constituents of the glomerular
basement membrane. These
include mutations affecting
the podocyte nucleus,
mito­chondria or lysosomes, the
slit diaphragm or actin
cytoskeleton, and the
glomerular basement
membrane. Nephrin, podocin,
and CD2AP, for example, are
essential components of a
zipper-like structure spanning
the interdigitating foot
processes of the podocyte, the
slit diaphragm and link directly
with the podocyte actin
cytoskeleton. The actin
cytoskeleton is further
supported by microfilaments
that maintain structural
stability and facilitate the
dynamic nature of the podocyte
structure and function. The
importance of these
microfilaments is evident as
mutations in both α-actinin 4
and INF2, which are involved in
actin regulation and
polymerisation lead to FSGS.
64
podocyte structure and function is dependent on
the molecular interplay between the network of
proteins that anchor the podocyte to the glom­
erular basement membrane and maintain its unique
structure, and also the crosstalk with the fenestrated
glomerular endothelium. Thus, any injury to the
Glomerular filtration barrier in nephrotic syndrome
Kidney
Nephron
Glomerulus
Glomerular
filtrate
Afferent
capillary
Efferent
capillary
Normal
Nephrotic syndrome
Pathogenesis
(a) Immune-mediated
(b) Systemic circulating factors (eg, suPAR)
(c) Podocyte related factors (eg, ANGPTL4)
(d) Genetic variants
Mutant proteins play roles in:
4 Actin
1 Nucleus
Urinary space
2 Mitochondria
5 Slit diaphragm
3 Lysosomes
6 Basement membrane
Podocyte
cell body
1
3
4
2
Slit diaphragm
5
Podocyte
effacement
Basement
membrane
6
Red
blood cell
White
blood cell
Fenestrated
endothelial
cells
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Seminar
podocyte has implications for the entire glomerular
filtration barrier.22
Immune mediated
It is suspected that dysfunction or dysregulation of
T lymphocytes are involved in the pathogenesis of NS
(figure 2).23–25 Supportive evidence includes the efficacy of
immunosuppressive agents in NS, spontaneous NS
remission following infection with measles,24 and the
resolution of NS following chemotherapy for Hodgkin’s
and other T-cell lymphomas, which can trigger or precede
NS.25 Lastly, development of NS after allergic reactions
to various stings and poisons suggests an immunemediated role in disease pathogenesis.
A recent molecular candidate for the cause of
podocytopathies and proteinuric states is CD80 (B7-1).
CD80, is a protein expressed on antigen-presenting cells
that provides the primary co-stimulatory signal for T-cell
activation via receptors on the T-cell surface. The T-cell
surface expresses protein receptor CTLA-4, which binds
CD80. An increase in podocyte B7-1 expression is
evident in a variety of animal models of proteinuria and
in human studies.26 This hypothesis was further tested
through the CTLA-4 mimicking therapeutic agents,
abatacept and belatacept in FSGS, but remains
controversial and clinical trials are under way.27,28
proteinuria, through an effect on either the glomerular
basement membrane or the endothelial cells, and by
affecting the charge of the glomerular filtration barrier,
which prevents albumin from traversing the barrier. In
contrast, a sialylated form is released into circulation
from other tissues and can mitigate proteinuria by
binding αvβ5 integrins on the glomerular endothelium.
Exploration of how sialylated ANGPTL4 could be used to
treat NS is ongoing, however, off-target effects, such
as inhibition of lipoprotein lipase leading to hyper­
triglyceridaemia in NS, could be exacerbated.32
Genetics
Genetic risk and SSNS
A genetic locus on chromosome 6p and single
nucleotide polymorphisms in HLA-DQA1 and HLADQB1 were substantially associated with SSNS using an
exome array.36 This locus, however, only explains
4∙6% of the genetic risk for SSNS.36 A common finding
from genome-wide association studies of glom­
erular diseases is the significant association with
polymorphisms from the major histocompatibility
complex. It is not clear whether the HLA loci are
causal, given the commonality among glomerular
studies, or it reflects the allele frequency by specific
ethnicity studied.36
Systemic circulating factors
Genetics and SRNS
A circulating glomerular permeability factor has been
hypothesised to cause NS, however, defining a single
putative factor remains elusive. The majority of studies
favour a circulating factor in SRNS or FSGS (figure 2).
A few studies demonstrate proof of a blood-derived
glomerular permeability factor. For example, serum
from patients with FSGS in pre-clinical and ex-vivo
studies induced proteinuria or increased permeability of
glomeruli to albumin.29 There was also successful
treatment of recurrent FSGS after kidney transplantation
with immuno­adsorption. Finally, maternal transmission
of FSGS confirmed a circulating factor.30 There are num­
erous factors proposed including heparanase, haemo­
pexin, angiopoietin-like 4 (ANGPTL4), cardiotrophin-like
cytokine-1 and, more recently, soluble urokinase plasmino­
gen activator receptor (suPAR).31–33 These factors might
impact glomerular permeability, possibly through effects
on the endothelial cell or podocyte.
suPAR affects the podocyte actin cytoskeleton via an
interaction with αvβ3-integrin receptor on the surface of
podocytes. Increased suPAR con­
centrations were
originally described in FSGS;34 however, suPAR as a
circulating factor has been refuted since concentrations
vary by kidney function, there is an absence of specificity
for FSGS, and findings are not easily reproducible.35
Two distinct forms of ANGPTL4, a glycoprotein and
acute phase reactant expressed in adipose tissue, the
heart, and skeletal muscle, are elevated in NS.32 A hypo­
sialylated form secreted from podocytes can lead to
Identifying genetic causes for children with SRNS early in
their course could allow discontinuation of immuno­
suppressive agents, aid in transplant management, and
provide information for prenatal counselling. Con­
firmation of a genetic defect generally implies a reduced
risk of recurrence afer transplantation, as it is likely
a kidney-specific disease. De novo auto-immune-mediated
NS can develop in the transplanted kidney owing to
neoantigens,37 especially among children with NPHS1
(nephrin) mutations.38 Depending on the age of onset of
SRNS, the likelihood of defining a monogenic cause
decreases as children age. Mutations in key podocyte
genes such as NPHS1, NPHS2, LAMB2, or WT1 explain
69–85% of cases of NS presenting in the first 3 months of
life and 50–66% of NS cases presenting between 4 and
12 months.39,40 After 1 year of age, the chance of identifying
a genetic cause for SRNS decreases substantially to
25% between the ages of 1 and 6 years, 18% between 7 and
12 years, and as low as 11% in those aged 13–18 years.39 In
an international registry of over 1340 children with SRNS
over 1 year of age, approximately 14% had a genetic
mutation.41 Over 30 genes are reported to be associated
with SRNS or FSGS, and the list is expected to expand
(appendix). Mutations in the mitochondrial genes involved
in biosynthesis of coenzyme Q10 leading to deficiency,
occur in 1% of cases of familial SRNS.39 Coenzyme Q10 is
an antioxidant and an essential component of the electron
chain and, most importantly, supplementation can be
effective for mitochondrial podocytopathies—a potentially
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See Online for appendix
65
Seminar
curative therapy. High-throughput next generation DNA
sequen­cing from patients with sporadic FSGS, targeting
all known podocyte genes, might identify other FSGS
susceptibility genes.42
Complications of nephrotic syndrome
Infection
Infection is the leading cause of morbidity and,
historically, mortality in children with NS.43 NS is
associated with low concentrations of immunoglobulin
G (IgG) from urinary loss and altered production, which
contributes to infection risk. Loss of complement can
also predispose to infection risk. Spontaneous bacterial
peritonitis, especially by Streptococcus pneumoniae,
remains a serious complication of NS, and a low serum
albumin (<15 g/L or 1∙5 g/dL) is associated with
increased risk of peritonitis.44 Routine antibiotic
prophylaxis for prevention of spontaneous bacterial
peritonitis in children with active NS is generally not
recommended owing to scarcity of evidence, although
some centres could opt for prophylaxis in children with
a history of peritonitis.45 Pneumococcal vaccination can
successfully be given to children with NS, even when
on steroid therapy, and is recommended by the
Children’s Nephrotic Syndrome Consensus Con­
ference.46,47 Children with NS are also at risk of
developing pneumonia from Streptococcus pneumoniae,
Haemophilus influenzae, Staphylococcus aureus, and
cellulitis, caused by Staphylococci, group A Streptococci,
and H influenzae species.45
Varicella-zoster infection poses a substantial risk to
children with NS. The vaccine is a weakened form of
the virus, which is typically best avoided in immuno­
compromised children. It appears to be safe, however,
for children who are in remission or who are on
low-dose alternate-day steroids, an optimised, two-dose
vaccination schedule has been developed.48 Prophylactic
varicella-zoster immune globulin (VZIG) is rec­
ommended for exposure to chickenpox. VZIG should
be given as soon as possible but can be given up to
10 days after exposure. Therapeutic intravenous
aciclovir could also be effective in NS, however, data are
scarce and extrapolated from solid organ transplant­
ation reports.49
Venous thromboembolism
NS is a well recognised hypercoagulable state in
which children are at risk of venous thrombo­
embolism (VTE) including cerebral sinus venous throm­
bosis, pulmonary embolism, and renal vein throm­bosis.50
VTE complicates an estimated 3% of cases of NS during
childhood.50,51 The pathophysiology of VTE in NS is multi­
factorial resulting from abnormalities in platelet aggre­
gation, increased synthesis of prothrombotic factors
(factors V and VIII), urinary loss of anticoagulant
proteins (antithrombin III, protein C and S), altered
fibrinolysis, and intra­vascular fluid depletion.52 Treatment
66
is with low-molecular-weight heparin. There is in­
sufficient evidence to warrant universal thrombosis
prophylaxis in childhood NS.50
Acute kidney injury (AKI)
AKI, an underappreciated complication, is now rec­ognised
as the third most important complication in children
treated in hospital with NS.53 Recently, a multicentre study
from the USA reported that 58∙6% of 336 children
admitted to hospital for NS had evidence of AKI with
identified risk factors such as concomitant infections, use
of nephrotoxic medications and SRNS.53 The use of
diuretics in a child with haemoconcentration and intra­
vascular volume depletion might predispose to AKI. Renal
vein thrombosis, acute tubular necrosis in the setting of
hypovolaemia and sepsis, and interstitial nephritis in­
duced by non-steroidal anti-inflammatory drugs or
antibiotics are also recognised contributors to AKI.
Dyslipidaemia
NS is associated with substantial abnormalities in lipid
metabolism, leading to hypercholesterolaemia, hyper­
triglyceridaemia, and various other lipoprotein abnor­
malities. Lipid abnormalities are primarily related to
urinary losses of key transport proteins including
albumin, which carries free cholesterol, and also a com­
pen­
satory increase in proteins involved in triglyceride
metabolism.54 It is unknown whether altered lipid
metabolism confers long-term cardiovascular risk from
atherosclerosis in children with NS. The use of lipidlowering agents for the dyslipidaemia in NS is not advised,
unless there is substantial persistent proteinuria with
extremely high levels of hypertriglyceridaemia. The
evidence of benefit is not clear and side-effects such as
liver dysfunction, risk of rhabdomyolysis, and delayed
growth and development although rare are not in­
substantial.55 If statins are initiated, it is only recommended
for children over the age of 10 years with monitoring of
liver function and creatinine kinase prior to initiating
therapy and after 4 weeks.56
Management
Oedema in nephrotic syndrome
Based on the pathogenesis of oedema in NS, one of the
primary strategies in the management of oedema is salt
and fluid restriction with addition of a loop diuretic for
severe or symptomatic oedema.57 The addition of an
albumin infusion, typically in combination with a loop
diuretic, is sometimes employed to induce diuresis and
natriuresis, especially if signs of intravascular underfilling
or severe oedema are present. Response to diuretics alone
might be blunted, especially in an underfilled state, where
there is activation of neurohormonal systems in an attempt
to maintain intravascular volume. Furthermore, furo­
semide is highly protein bound and, in a hypoalbuminaemic
state, the volume of distribution substantially increases
with less drug available to reach the proximal tubule for
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secretion into the urinary space. The combined use of
albumin and furosemide remains controversial. Many
studies involved small numbers of patients, were largely
uncontrolled, and, in most, only a small benefit of diuresis,
natriuresis, and weight loss were observed with the
combination of furosemide and albumin over furosemide
alone. Approximately 25% of children with NS might
actually be hypovolaemic at presentation, as assessed by
clinical, laboratory, and echocardiographic parameters.58
Diuretics alone might aggravate hypovolaemia and
intravascular depletion, thus, the use of albumin could be
warranted. Care should be taken with the administration
of albumin in children who are not exhibiting signs of
hypovolaemia, as the resultant expansion in intravascular
fluid could precipitate pulmonary oedema.57
Management of nephrotic syndrome
Standardising management of NS has been hampered
by the paucity of high-quality trial evidence supporting
international guidelines. This lack of evidence has
resulted in substantial variation in care based on
physicians’ preference, drug availability by country, and
interpretation of the sparse trial data. Substantial
physician variability in choice of steroid-sparing agents
for children with NS is described in Europe, Canada,
and the USA.59,60 In the following section, we outline the
principal treatments for NS (figure 3). Certain agents,
such as mizoribine, or chlorambucil with restricted
availability are not discussed in detail.1 Baseline and
additional investigations, as well as considerations
for genetic testing and renal biopsy are presented
in panel 3.
Initial therapy
Standard therapy is at least 4–6 weeks of steroids each
day (prednisone or prednisolone), followed by a mini­
mum of 6 weeks of alternate day therapy based on
evidence from clinical trials.1 Many published protocols
by guideline, centre, or country highlight the variability
in the prednisone taper (table).
Until recently, a Cochrane review strongly suggested that
6 months of therapy was superior to 2–3 months, owing to
a substantial reduction in relapses after initial presentation
of NS. The meta-analysis of randomised controlled trials
(RCTs) involved over 700 children.64 Since 2013, three RCTs
demonstrated that extending treatment to 6 months
compared with 2–3 months did not reduce the risk
of relapse, the development of frequent relapses, or
steroid dependence and the eventual need for an additional immunosuppressive agent.65–67 Thus, treatment
with steroids for 6 months is no longer recommended.68
Chronic steroid use is associated with many side-effects
including obesity, cushingoid features, striae, ocular
complications, such as cataracts and glaucoma, metabolic
features, musculoskeletal features, such as osteoporosis
and avascular necrosis of the head of the femur, and
behavioural features. In those that continue to relapse
www.thelancet.com Vol 392 July 7, 2018
FRNS
or SDNS
SSNS
Low dose
alternate day
steroids
Infrequent
relapses
Ongoing relapses
or steroid toxicity
Cyclophosphamide
or levamisole
Long-term
remission
Steroids
No response after
8 weeks of steroids
SRNS
Ongoing relapses
or steroid toxicity
Biopsy every
2–3 years
Tacrolimus or
mycophenolate mofetil
Ongoing relapses
or steroid toxicity
Biopsy every
2–3 years
Rituximab ± other
immunosuppressants
Tacrolimus
Genetic cause
confirmed
No response
ACE inhibitor
ARB
Progression over time to ESRD
Figure 3: Principal treatments for nephrotic syndrome at diagnosis and follow-up
After initial therapy with steroids, children are classified as having SSNS or SRNS after at least 8 weeks of therapy.
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
and the child continues to relapse or is steroid dependent, then a calcineurin inhibitor is often the next agent, or
mycophenolate mofetil. The scarcity of trial evidence has resulted in substantial variation in choice of steroid-sparing
agents based on physicians’ preference, drug availability by country, and cost. SSNS=steroid sensitive nephrotic
syndrome. SRNS=steroid resistant nephrotic syndrome. FRNS=frequently relapsing nephrotic syndrome.
SDNS=steroid dependent nephrotic syndrome. ACE=angiotensin converting enzyme inhibitor. ARB=angiotensin
receptor blocker.
and require steroids into adulthood, osteo­
porosis and
being overweight cause substantial morbidity.9
Treatment of frequently relapsing nephrotic syndrome
(FRNS) or steroid-dependent nephrotic syndrome
(SDNS)
For relapses of SSNS, the efficacy of steroids is not in
doubt; however, tapering schedules remains controversial,
as data are scarce.1,64 KDIGO recommends a tailored
approach to steroid therapy depending on whether
children relapse either infrequently or frequently (table).1
Triggers of relapse
Additional factors triggering relapses include allergies and
infection. Treatment for allergies with dietary restrictions,
skin desensitisation, mast cell stabilisers such as disodium
cromoglycate demonstrate little benefit in preventing
relapsing disease.69 On the contrary, several trials suggest
that relapses might be reduced if prednisolone is
administered daily for 5–7 days at the onset of upper
respiratory tract infection in FRNS or SDNS. Although
studies have a high risk of bias owing to small sample
sizes and variability in study design, treatment is still
recommended by the KDIGO guide­
lines.1,70–72 A large,
placebo-controlled, multicentre trial of 300 children in the
UK (PREDNOS 2) will clarify the effectiveness and safety
of this approach when completed.73
67
Seminar
Year of
publication
International
Arbeitsgemeinschaft
Study of Kidney
für Pädiatrische
Disease in Children Nephrologie (APN)2
(ISKDC)61
Haute Autorité de Santé
(France)62
Italian Society for
Pediatric Nephrology
(SINePe)63
KDIGO Glomerulonephritis
Guidelines1
Hospital for Sick Children
(Toronto, Canada)11
1970
2008
2017
2012
2016
60 mg/m² per
day × 6 weeks
(maximum 60 mg in
single or 2 divided
doses)
60 mg/m² per day or 2 mg/kg
per day × 4–6 weeks (maximum
60 mg)
60 mg/m² per day × 6 weeks
(maximum 60 mg in single
morning dose)
60 mg/m² per alternate
day × 8 weeks (maximum 60 mg)
followed by a 15 mg/m² per
alternate day × 15 days and
continue to wean. In addition,
3 methylprednisolone pulses if
proteinuria persists after 1 month
of daily prednisone therapy
40 mg/m² per
alternate day × 6 weeks
(single dose; maximum
40 mg) without
tapering
40 mg/m² per alternate day or
1∙5 mg/kg/alternate day
(maximum 40 mg ) × 6–8 weeks
(at least 12 weeks) and
continued for 2–5 months with
tapering
40 mg/m² per alternate
day × 6 weeks
(maximum 60 mg), 30 mg/m²
per alternate day × 8 days
(maximum 30 mg), 20 mg/m²
per alternate day × 8 days
(maximum 20 mg), 10 mg/m²
per alternate day × 12 days
(maximum 10 mg)
1988
Initial presentation
60 mg/m² per day × 4 weeks
60 mg/m² per
day × 6 weeks (maximUm (maximum dose 60 mg)
dose 80 mg)
Initial dose
and
duration
60 mg/m² per
day × 4 weeks
Subsequent
dose and
tapering
40 mg/m² per
4 weeks of
alternate day × 6 weeks
40 mg/m²
per alternate day but (maximum dose 60 mg)
given on
3 consecutive days
out of a week
Relapses
Starting
dose and
duration
··
··
60 mg/m² per day until urine
protein is negative for 6 days
60 mg/m² (max 60 mg
in a single or 2 divided
doses) until urine
protein is negative for
5 days
60 mg/m² per day or 2∙0 mg/kg
per day (maximum of
60 mg/day) until urine is
negative for 3 days
60 mg/m² per day until urinary
protein is trace or negative for
5 consecutive days
Follow-up
dose and
duration
··
··
60 mg/m² per alternate
day × 4 weeks, 45 mg/m² per
alternate day × 4 weeks,
30 mg/m² per alternate
day × 4 weeks, 15 mg/m² per
alternate day × 4 weeks
40 mg/m² per
alternate day (max
40 mg) × 4 weeks
40 mg/m² or 1∙5 mg/kg/
alternate day (maximum
40 mg) × 4 weeks (minimum)
60 mg/m² per alternate
day × 8 days (maximum
60 mg/day), 50 mg/m² per
alternate day × 8 days
(maximum 50 mg/day),
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
relapses
··
··
60 mg/m2 per day or
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
In general, the first step in managing a child with
frequent relapses is to maintain them on low-dose,
alternate-day steroid, typically at the lowest dose possible,
or just above the steroid dose associated with the latest
relapse. Children could be treated with steroid-sparing
agents when low-dose alternative-day steroid therapy
fails or when severe adverse effects of steroids develop
(figure 3). The decision to choose steroid-sparing treat­
ments should be based on drug efficacy, side-effects and
the patient’s condition. Also, regional availability of
68
medications and physician preferences greatly influence
choice of steroid-sparing medication (panel 4).59,60 We
provide the list of agents below based on the strength of
evidence (figure 3).
Steroid-sparing agents
Levamisole, an antihelminthic agent, has immuno­
modulatory properties and a favourable side-effect profile.
Levamisole reduced the risk of relapse compared with
placebo or no treatment.74,75 There was, however, con­
siderable heterogeneity in study design described in a
www.thelancet.com Vol 392 July 7, 2018
Seminar
meta-analysis.76 An international, multicentre, doubleblind, placebo-controlled, RCT of levamisole in SSNS
found that 6% of patients on placebo versus 26% on
levamisole were in remission at 1 year.103
Cyclophosphamide, the most commonly used steroidsparing agent, is effective in multiple RCTs for the
treatment of FRNS and SDNS.78–81 A Cochrane review
reported that cyclophosphamide substantially reduced
the relapse risk at 6–12 months by 56% when compared
to prednisolone alone (relative risk [RR] 0∙44, 95% CI
0∙26–0∙73).76 A meta-analysis reported that studies for
non-steroid-dependent FRNS resulted in remission in
72% of patients after 2 years and 36% after 5 years,
whereas the proportions for SDNS were 40% and 24%,
respectively.43 Studies to date used various definitions
of response, which leads to hetereogeneity in re­
ported outcomes.
Important side-effects of cyclophosphamide include
gonadal dysfunction (azoospermia in boys), myelo­
suppression (leucopenia), infection, alopecia, haemor­
rhagic cystitis, and hepatic dysfunction. Meta-analyses
report that risk of azoospermia is higher in boys of
pubertal age (Tanner stage 2 or greater) or post-pubertal
age, especially when the cumulative dose of cyclo­
phosphamide ranges from 100 to 300 mg/kg, but higher
doses could be safe in pre-pubertal boys.43,104 In NS,
substantially lower doses of cyclophosphamide are
prescribed typically, 2–2∙5 mg/kg on average for
8–12 weeks, with a maximum daily dose of 100 mg and
only as a single course.1 The risk of female infertility is
documented to be lower than in boys, and a cumulative
dose up to 200 mg/kg is reported safe105 as infertility
occurred at a dose of 300 mg/kg or higher.104 Approxi­
mately 32% of NS patients developed leucopenia, during
cyclophosphamide therapy.43 Therefore, if the leucocyte
count drops below 4500 cells per μL, a lower dose could be
used or suspended if the leucocyte count falls below
3000 cells per μL.43 Long-term studies with decades of
follow-up are needed to understand long-term risk of
cyclophosphamide.
Panel 4: Steroid-sparing agents for frequently relapsing
nephrotic syndrome (FRNS) or steroid-dependent
nephrotic syndrome (SDNS)
Levamisole
• Reduces risk of relapse compared with placebo or no
treatment;74,75 there was, however, considerable
heterogeneity in the meta-analysis76
Cyclophosphamide
• Effective for FRNS,76,77,79 but less so for steroid-dependent
nephrotic99 syndrome;43,79–81,82 however, there is overlap in
the classification
Ciclosporin
• Effective for FRNS or SDNS,83–90 but many patients suffer
relapses after discontinuation of ciclosporin therapy
(ciclosporin dependence)85,86,89–91
Tacrolimus
• Several case series suggest that tacrolimus is effective for
FRNS or SDNS,92–96 but there are no randomised controlled
trials
Mycophenolate mofetil
• Less effective than ciclosporin,97,98 but has a favourable
side-effect profile
Rituximab
• Rituximab and lower doses of prednisone and calcineurin
inhibitors are non-inferior to standard doses of these
agents in maintaining short-term remission in children
who show dependence on both drugs, and allow their
temporary withdrawal99
• Effective for complicated FRNS or SDNS, but all children
had relapses by 19 months after rituximab infusion100
• Non-inferior to steroids in maintaining remission in SDNS101
Mizoribine
• Not effective for SDNS, but a subgroup analysis of
children aged 10 years and younger demonstrated that
the proportion of patients who relapsed was substantially
lower in the mizoribine group than the placebo group102
Calcineurin inhibitors
Ciclosporin is effective for both FRNS and SDNS.83–87
Blood concentration of ciclosporin should be monitored,
usually by trough levels or C2 (at 2 h post-dose) levels,
and the dose should be adjusted within target
levels (trough levels: 60–100 ng/mL; C2 levels:
300–700 ng/mL).83,84,88 There is, however, no international
consensus on target con­
centrations owing to incon­
clusive evidence.1 In Japan, dose is adjusted to maintain
trough concentrations within 80–100 ng/mL for the first
6 months, and within 60–80 ng/mL for the next
18 months, and in North America, reported levels range
from 50 to 100 ng/ml.85,86,91 Additionally, the length of
therapy is not well defined as children frequently
relapse after discontinuation of the drug (ciclosporin
dependence).85,86,91 Nephrotoxicity is also problematic with
www.thelancet.com Vol 392 July 7, 2018
increasing risk after prolonged use of the drug for 2 years
or more.106,107
Tacrolimus could be considered when ciclosporin
cannot be used owing to cosmetic side-effects, including
hypertrichosis and gingival hypertrophy. Both medi­
cations are now generic, thus cost should not be an issue.
Potential onset of diabetes and nephrotoxicity are
important side-effects. No definitive dosing for tacro­
limus is established, but it typically starts at 0∙1 mg/kg
per day (range 0∙05–0∙2).97,98,108 Optimal trough con­
centrations are not defined but ranges from 5 to 8 ng/mL
have been reported, and persistent levels greater
than 8 ng/mL were associated with increased risk of
nephrotoxicity in a single study.93,94 Hypertension could
also be worsened with calcineurin inhibitors and
69
Seminar
could potentiate the development of posterior reversible
encephalopathy syndrome.108
Mycophenolate mofetil (MMF)
Mycophenolate mofetil (MMF) is used as a steroidsparing agent for FRNS or SDNS owing to the favourable
side-effect profile and absence of nephrotoxicity.
Physician preference for MMF stems from the concerns
about the toxicity of cyclophosphamide and calcineurin
inhibitors; however, trial evidence is scarce. A randomised,
multi­centre, open-label, crossover study comparing the
efficacy and safety of a 1-year treatment with MMF or
ciclosporin in 60 pediatric patients with FRNS, reported
more relapses per patient per year with MMF than with
ciclosporin.96 Similar results were reported in another
multicentre RCT comparing the efficacy of MMF to that
of ciclosporin in 24 children with FRNS and biopsyproven MCD.98 A French study that employed Bayesian
techniques and probability in 23 children, found that
MMF could reduce the number of relapses and steroid
doses, suggesting use of MMF prior to cyclophosphamide
or ciclosporin.109 Recent studies demonstrate efficacy at
higher doses, which are not routinely monitored and
typically used in kidney transplant­ation. Maintaining an
area under the curve for myco­phenolic acid, assessed by
pharmacokinetic studies higher than 45 mg × h per L,
might be associated with less frequent relapses.110
Rituximab
Rituximab, a chimeric anti-CD20 monoclonal antibody,
is effective and allows for discontinuation or reduction
of steroids and other steroid-sparing agents in NS. An
initial open-label RCT concluded that rituximab and
lower doses of prednisone and calcineurin inhibitors are
non-inferior to standard therapy in maintaining shortterm re­mission.99 Findings were confirmed by a multi­
centre, double-blind, randomised, placebo-controlled
trial that assessed efficacy and safety of rituximab versus
placebo in 48 children with complicated FRNS or
SDNS.100 Those on rituximab received 375 mg/m² body
surface area (maximum 500 mg) once weekly for
4 weeks, and the placebo group received placebo at
similar frequency. Prednisolone was gradually tapered
after remission was achieved. Tapering of ciclosporin
was started on day 85, and discontinued by day 169. The
50% relapse-free period (267 vs 101 days; hazard ratio
[HR] 0∙267, 95% CI 0∙135–0∙528, p<0∙0001), and the
daily steroid dose was substantially lower in those on
rituximab than placebo (9∙12 [SD 5∙88] vs 20∙85
[SD 9∙28] mg/m² per day, p<0∙0001) up to 1 year. In
follow-up, all children relapsed by 19 months, suggesting
that the benefit of rituximab was not permanent. Re­
cently, rituximab was also shown to be non-inferior to
steroids in maintaining remission in patients with
SDNS never exposed to a calcineurin inhibitor and who
had not received either MMF or cyclophosphamide in
the preceding 6 months.101
70
Rituximab is generally safe and well tolerated in most
children; however, potentially serious adverse events
include persistent low B cell and failure to repopulate,
depletion of memory B cells , and a risk of hypo­
gammaglobulinaemia, occasionally requiring infusions
of immunoglobulin. Rarer adverse events are also report­
ed, including fatal hepatitis induced by reactivation
of hepatitis B virus, progressive multifocal leuko­
encephalopathy, pulmonary fibrosis, fulminant myo­
carditis,111 pneumocystis pneumonia,112 immune-mediated
ulcerative colitis, and agranulocytosis. Recently, hyper­
sensitivity reactions were reported with autoantibodies to
rituximab during the second course of rituximab.113
Despite the benefit of rituximab, residual issues require
further study such as the total number of infusions,
whether to redose every 6 months or base dose on
repopulation of CD20 B cells. Importantly, we need to
understand the long-term consequences of rituximab
therapy in children as treatment is considered earlier in
disease course.
Treatment for steroid-resistant nephrotic syndrome
Identification of a podocyte gene defect is fundamental to
determining treatment response to steroids and calci­
neurin inhibitors as demonstrated in recent studies.114,115
SRNS with no proven genetic mutation is expected to
respond with complete remission in up to 60% of cases
and with partial remission in up to 19%.114,115 Furthermore,
those with no genetic mutation have a substantial
advantage in terms of kidney survival over 10 years, with
ESRD occurring in 71% of those with a genetic disease
versus 29% in those without.114
Calcineurin inhibitors such as ciclosporin and tacro­
limus are recommended as initial therapy for children
with SRNS,1,116 with cumulative complete and partial
remission in ciclosporin treatment substantially better
than placebo.117–119 Also, tacrolimus is similar to ciclosporin
in combination with low-dose steroids in inducing
remission in patients with SRNS.120 Optimal duration of
calcineurin inhibitor therapy is still unknown, although
KDIGO guidelines recommended a minimum of
12 months,1 and in clinical practice, can be con­
tinued up to 24 months. Combination therapy in­
volving steroid pulse therapy and ciclosporin could be
considered effective in inducing remission of SRNS in
extreme cases.121,122
Two RCTs demonstrated a substantial reduction in
proteinuria with enalapril123 and fosinopril.105 KDIGO
therefore recommended angiotensin-converting enzyme
inhibitors or angiotensin II receptor blockers for children
with SRNS.1
Cyclophosphamide has no benefit for SRNS.78,124 MMF
use in the treatment of SRNS has been described and the
proportion of patients in remission is low.125–127 A recent
randomised trial of 138 children evaluated dexamethasone
plus MMF as a therapy for patients with steroid-resistant
FSGS versus ciclosporin, and found no significant
www.thelancet.com Vol 392 July 7, 2018
Seminar
difference in achieving partial or complete remission
at 1 year; however, the trial was substantially under­
powered.128 Several case series suggested that rituximab is
effective with refractory (failing to respond to calcineurin
inhibitors) SRNS; however, an open-label, randomised
trial of rituximab failed to demonstrate an improvement
in 31 children with SRNS, compared to either 16 children
who received calcineurin inhibitors, prednisolone, and
two infusions of rituximab, or 15 children who received
calcineurin inhibitors and prednisolone alone.129
Controversies, uncertainties, and outstanding
research questions
There are many remaining questions about NS and these
can be grouped into understanding: (1) who develops NS
and what is the cause?; (2) factors contributing to
interindividual variability in response to medications;
and (3) specific triggers leading to relapsing disease.
There are several controversies and uncertainties. What
is the expected dose of calcineurin inhibitors that will
induce and maintain remission? When should we
discontinue calcineurin inhibitors in children who
maintain remission? What is the role of MMF and
rituximab? Well designed RCTs need to be conducted to
clarify these uncertainties. Additionally, there is a need for
optimal trials to address novel treatments and tapering
regimens, and follow-up studies to address potential longterm risk of medications, especially among those who
receive biological agents. For complicated FRNS or SDNS,
further modification of rituximab treat­
ment, including
adjunct immunosuppressive therapies and repeated
courses of rituximab, might be necessary to extend the
relapse-free period. Finally, a comparison of the efficacy,
safety, and cost-effectiveness of various rituximab dosing
regimens and B-cell-driven regimens are needed.
There is also a need to develop novel therapies to
address refractory disease and FSGS. Several therapies
are in the research phase, including sirolimus, apheresis,
adalimumab, fresolimumab, rosiglitazone, galactose at
high dose, and ofatumumab (appendix). Finally, a
determination of the social and patient-centred factors
that affect outcomes will aid in counselling children and
families about long-term prognosis.
Conclusion
Although, there is substantial morbidity due to chronic
use of steroids and other steroid-sparing agents, less than
5% of children with SSNS progress to ESRD. Steroid
resistance, however, is an important determinant of future
risk for ESRD.8 Historically, more than 90% of children
with NS enter long-term remission after puberty,6,7
however, the precise number is not known, especially in
frequent relapsers or those on steroid-sparing agents with
the potential of active disease in adulthood.8–10
Contributors
DGN and RP conducted the literature search with initial manuscript
preparation. All authors contributed equally to data interpretation,
www.thelancet.com Vol 392 July 7, 2018
writing of the manuscript, and construction of the figures, panels, and
tables. All authors reviewed and approved the final version.
Declaration of interests
DGN declares no competing interests. KI has received grants from
Novartis Pharma, Japan Blood Product Organization, AbbVie,
JCR Pharmaceuticals, Daiichi Sankyo, Teijin Pharma, CSL Behring, Novo
Nordisk Pharma, Air Water Medical, Astellas Pharma, Takeda
Pharmaceutical, Taisho Toyama Pharmaceutical, Eisai, and Biofermin
Pharmaceutical, and lecture fees or consulting fees, or both from Zenyaku
Kogyo, Novartis Pharma, Chugai Pharmaceutical, Astellas Pharma,
Springer Japan, Meiji Seika Pharma, Asahi kasei Pharma Corporation,
Medical Review, Nippon Boehringer Ingelheim, Baxter Limited, Ono
Pharmaceutical, Sanwa Kagaku Kenkyusho, Sanofi, Alexion Pharma, and
Kyowa Hakko Kirin. RP has received grants from Astellas Pharma.
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