Review

Management of steroid-resistant nephrotic syndrome in

children and adolescents
Kjell Tullus, Hazel Webb, Arvind Bagga

More than 85% of children and adolescents (majority between 1–12 years old) with idiopathic nephrotic syndrome Lancet Child Adolesc Health 2018
show complete remission of proteinuria following daily treatment with corticosteroids. Patients who do not show Published Online
remission after 4 weeks’ treatment with daily prednisolone are considered to have steroid-resistant nephrotic October 17, 2018
http://dx.doi.org/10.1016/
syndrome (SRNS). Renal histology in most patients shows presence of focal segmental glomerulosclerosis, minimal
S2352-4642(18)30283-9
change disease, and (rarely) mesangioproliferative glomerulonephritis. A third of patients with SRNS show mutations
Nephrology Unit, Great
in one of the key podocyte genes. The remaining cases of SRNS are probably caused by an undefined circulating Ormond Street Hospital for
factor. Treatment with calcineurin inhibitors (ciclosporin and tacrolimus) is the standard of care for patients with Children, Great Ormond Street,
non-genetic SRNS, and approximately 70% of patients achieve a complete or partial remission and show satisfactory London, UK (K Tullus MD,
H Webb BSc) and Division of
long-term outcome. Additional treatment with drugs that inhibit the renin–angiotensin axis is recommended for
Nephrology, Indian Council of
hypertension and for reducing remaining proteinuria. Patients with SRNS who do not respond to treatment with Medical Research Advanced
calcineurin inhibitors or other immunosuppressive drugs can show declining kidney function and are at risk for end- Center for Research in
stage renal failure. Approximately a third of those who undergo renal transplantation show recurrent focal segmental Nephrology, All India Institute
of Medical Sciences, New Delhi,
glomerulosclerosis in the allograft and often respond to combined treatment with plasma exchange, rituximab, and
India (Prof A Bagga MD)
intensified immunosuppression.
Correspondence to:
Dr Kjell Tullus, Nephrology Unit,
Introduction prednisolone at a dose of 60 mg/m² daily for 4 weeks. Great Ormond Street Hospital for
Nephrotic syndrome is diagnosed based on a triad of Others recommend treatment for 8 weeks.2–4 Several Children, Great Ormond Street,
London WC1N 3JH, UK
symptoms: severe proteinuria (>1 g/m² per day), centres, including the Great Ormond Street Hospital for
kjell.tullus@gosh.nhs.uk
hypoalbuminaemia (albumin <2·5 g/dL), and oedema. Children, London, UK, administer three intra­ venous
Most children older than 1 year (generally until 12 years pulses of methylprednisolone (500 mg/m²) before
old) are diagnosed with idiopathic nephrotic syndrome regarding patients as resistant.5 Steroid resistance most
based on these features and little else. A secondary cause often occurs during initial treatment with prednisolone
(eg, systemic lupus erythematosus and Henoch- (initial resistance), but can also occur during treatment
Schönlein purpura) is rare. for a relapse, in a patient who had previously responded
Idiopathic nephrotic syndrome presents as an acute to treatment with steroids or with a second-line drug
disease, with substantial proteinuria and increasing (late resistance). Steroid resistance is an important deter­
oedema. A smaller proportion of patients have a slower minant of future risk for end-stage renal disease.
and more atypical onset, sometimes over several months
or even years. Atypical features include onset in infancy
or adolescence, symptoms suggestive of an inflam­ Key messages
matory kidney disease, renal failure, hypertension, and • About 10–15% of children with idiopathic nephrotic syndrome who do not show
macroscopic haematuria. complete remission of proteinuria following 4 weeks’ treatment with corticosteroids
More than 85% of patients with idiopathic nephrotic are considered to have steroid-resistant nephrotic syndrome
syndrome respond (ie, complete remission of proteinuria • For 30% of patients with steroid-resistant nephrotic syndrome, the condition results
and normal serum albumin) following treatment with from a genetic cause; for the remainder, the disease is probably caused by a circulating
prednisolone.1 Response to prednisolone is an important factor
prognostic indicator for survival of kidney function. • Renal histology shows minimal change disease and focal segmental glomerulosclerosis
Although many patients with steroid-sensitive nephrotic (FSGS) in most patients
syndrome have frequent relapses or steroid dependence, • Approximately 50–70% of patients with steroid resistance show complete or partial
the long-term outlook for kidney function is favourable. remission following treatment with a calcineurin inhibitor (either ciclosporin or
The main long-term problem in these patients is the risk tacrolimus)
of side-effects from prolonged treatment with cortico­ • Although additional treatment with mycophenolate mofetil or rituximab is
steroids and other immuno­suppressive medications. considered in children who are resistant to treatment with steroids and calcineurin
Patients who do not respond to prednisolone are inhibitors, their efficacy to induce remission is low
considered to have steroid-resistant nephrotic syndrome • Patients with a genetic FSGS or those who do not show complete or partial remission
(SRNS). The medical community has not yet reached a following treatment with calcineurin inhibitors have high risk of end-stage renal failure
consensus regarding the length of time prednisolone • Patients with late resistance and absence of a genetic cause show high risk of recurrent
should be given before regarding a patient as steroid FSGS in the renal allograft
resistant. We recommend that steroid resistance should • Intensification of treatment with ciclosporin or tacrolimus, and combined treatment
be considered in patients who do not show complete with rituximab and plasma exchange might prevent or treat recurrent FSGS effectively
remission of proteinuria despite treatment with

www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9 1

 Review
Congenital nephrotic syndrome refers to infants with
onset of nephrotic syndrome before 3 months of age.
Most of these patients have mutations involving the
podocyte proteins (nephrin, podocin, and WT1) and do
not respond to treatment with steroids and other
medications. The course of illness is progressive and
most patients require renal replacement treatment in the
first decade. We have not included the clinical manage­
ment of these children in this Review.
Cause of SRNS
Genetic causes
The medical community has learnt much about the
genetic causes for SRNS over the past decades. Mutations
in more than 70 genes encoding key podocyte proteins
are recognised to cause the illness. Despite recognition
of an increasing number of genetic causes, only
30% of patients with sporadic SRNS show a defined
mutation.6
Genes associated with the occurrence of SRNS are
broadly classified as involving: structural elements of the
A
B
Figure 1: Kidney biopsy images of patients with SRNS
(A) Glomerulus in minimal change disease appear normal on light microscopy.
Tubules and interstitium are normal. Haematoxylin and eosin (H&E),
magnification 40×. (B) Focal segmental glomerulosclerosis. Segmental sclerosis
is noted in a perihilar location with hyalinosis. Evidence of tubular atrophy and
interstitial fibrosis is also present. H&E, magnification 20 ×.
2 www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9
slit diaphragm (NPHS1, NPHS2, CD2AP, and PLCE1);
cytoskeleton (ACTN4, MHY9, MYO1E, INF2, and actin
regulatory genes); glomerular basement membrane and
matrix proteins (LAMB2, ITGA3, and COL4A3–5);
mitochondrial proteins (COQ2, COQ6, and ADCK4);
nuclear proteins (WT1, LMX1B, NUP93, NUP107,
NUP205, and SMARCAL1); and other intracellular
proteins (TRPC6, SCARB2, APOL1, DGKE, CUBN,
and GAPVD1) with a wide spectrum of illness.
Nephrotic syndrome might also be associated with
syndromic features with mutations in specific genes—
eg, Denys-Drash syndrome and Frasier syndrome (WT1);
Pierson syndrome (LAMB2); nail-patella syndrome
(LMX1B); Epstein syndrome, Sebastian syndrome, and
related illnesses (MYH9); MELAS syndrome and Leigh
syndrome (mitochondrial genes); Galloway-Mowat syn­
drome (WDR73); and Schimke dysplasia (SMARCAL1),
as reviewed by Bierzynska and colleagues6 and Preston
and colleagues.7
Circulating factor
The probable cause for most patients with non-genetic
SRNS is thought to be a circulating factor.8,9 Circum­
stantial evidence exists that makes this theory quite
probable, but it has been elusive to define the circulating
factors responsible for SRNS.10 A large proportion of
children with non-genetic SRNS relapse quickly after
kidney transplantation: these patients often respond to
plasma exchange or immune adsorption. Small animals
infused with patient plasma, whole or its fractions, also
develop proteinuria. In 1975, a vascular permeability
factor was described.11 Other important suggestions of
circulating factors include haemopexin, interleukin-13,
cardiotrophin-like cytokine-1, and soluble urokinase-type
plasminogen activator receptor.12–15 None of these sug­
gested factors have been confirmed by independent
research groups so far.
Kidney biopsy
Renal histology is an important tool for diagnostic and
prognostic categorisation. Biopsies should be examined
by light, immunofluorescence, and electron microscopy
to define their histological features. An ade­quate biopsy
should have approximately 25 glomeruli, especially when
evaluating lesions that are focal or segmental. Biopsies
with fewer glomeruli have low diagnostic accuracy.
Common histological diagnoses include focal seg­
mental glomerulosclerosis (FSGS) in 35–55% of patients,
minimal change disease in 25–40% of patients, and
idiopathic mesangioproliferative glomerulonephritis in
10–15% of patients (figure 1).16 In about 20% of patients,
the histology shows membranous nephropathy,
immunoglobulin A nephropathy, or proliferative glome­
rulonephritis. We do not discuss their management in
this Review.
Data from the 21-nation multiethnic PodoNet Registry
have provided important information on the course and
 Review

outcome of a large cohort of children with SRNS.4

Clinical features were similar in patients with minimal Panel 1: Clinical tests for children with steroid-resistant nephrotic syndrome
change disease, FSGS, and mesangioproliferative glome­ Main tests
rulonephritis. Repeat biopsies, in 171 patients, found that • Blood creatinine, electrolytes, protein, albumin, transaminases
the diagnosis changed from minimal change disease to • Full blood count
FSGS in 26 of 47 (55%) cases, and from mesangio­ • 24 h urine protein excretion, spot urine protein to creatinine ratio (or albumin to
proliferative glomerulonephritis to FSGS in 16 of 33 creatinine ratio)
(48%) cases.4 • Varicella antibody status, measles immunoglobulin G (if no history of the measles,
Patients with SRNS mostly require treatment with mumps, and rubella vaccination)
calcineurin inhibitors that can cause nephrotoxicity,
which is characterised histologically by microvascular Additional tests
ischaemia and striped interstitial fibrosis.17 • Streptococcal antibodies, complement C3, C4 (if suspected lupus nephritis)
• Antinuclear antibody, anti-double stranded DNA antibody (if suspected lupus
Evaluation nephritis)
Treatment of SRNS should start with a re-evaluation of • Hepatitis C and B serology, HIV antibody
the diagnosis. Does the child have idiopathic nephrotic • Kidney biopsy: light, immunofluorescence, and electron microscopy
syndrome with a probable biopsy diagnosis of minimal Genetic studies (targeted exome sequencing) indications
change disease or FSGS, or are there atypical features? • Congenital (onset<3 months of age), infantile-onset nephrotic syndrome, family
Evaluation should include a detailed investigation of history of steroid resistance, suspected syndromic forms, resistance to calcineurin
current metabolic status and an underlying cause inhibitors, and before transplantation
(eg, proliferative glomerulonephritis; panel 1). Patients
require regular monitoring for severity of proteinuria
and blood concentrations of creatinine and albumin. Child with typical nephrotic syndrome:
Experts recommend a renal biopsy in all patients to treatment with prednisolone for 4 weeks
counsel parents and guide treatment. Screening for
variations in known genes for SRNS is important,
especially in infants with initial resistance, familial or
Remission achieved No response:
syndromic FSGS, non-response to treatment with start CNI—aim to treat for
calcineurin inhibitors, and before transplantation. 3–6 months and send genetic screen
(for primary steroid resistant)

Treatment
Although the aim of treatment in SRNS is the Manage as steroid-sensitive Response to CNI: complete No response to CNI
achievement of complete remission, the occurrence of nephrotic syndrome remission
even partial remission is satisfactory.18,19 Complete
remission is defined as presence of trace or negative
proteinuria (by dipstick) or spot urine protein to
Genetic screen negative: Genetic screen positive: consider
creatinine ratio less than 0·2. Patients are considered to consider adding in MMF or stopping immunosuppression
be in partial remission if they show proteinuria level of rituximab
1–2+ (urine protein:urine creatinine from 0·2–2), serum
albumin more than 2·5 g/dL, and no oedema. Persistence
Remission achieved: No response to increased High chance of development of
of 3–4+ proteinuria (urine protein:urine creatinine more decreased chance of develop- immunosuppression ESRD: consider supportive
than 2), albumin less than 2·5 g/dL, or oedema ment of ESRD and high chance measures
of relapse
constitutes non-response.
Calcineurin inhibitors (ciclosporin and tacrolimus)
with low-dose prednisolone are recommended as the Figure 2: Flow chart schematically outlining clinical management for a child with steroid-resistant nephrotic
syndrome
main treatment for children with SRNS (figure 2). CNI=calcineurin inhibitor. MMF=mycophenolate mofetil. ESRD=end-stage renal disease.
Evidence-based role for treatment with other drugs,
including cyclophosphamide, myco­ phenolate mofetil,
and rituximab, is scarce. The optimal duration of occurrence of partial remission following treatment,
treatment with calcineurin inhibitors is not clear. most experts do not recommend that patients with a
Guidelines from Kidney Disease Improving Global confirmed mutation in podocyte genes receive
Outcomes recommend a minimum duration of immunosuppressive medi­cations.19
12 months;2 in practice, treatment is often continued for
24–36 months. Calcineurin inhibitors
The question whether children with a proven genetic Although the immunosuppressive effect of calcineurin
cause should receive immunosuppressive treatment is inhibitors is through inhibition of T lymphocytes, a
being debated. Although anecdotal reports suggest direct effect of ciclosporin on the podocyte actin

www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9 3

 Review

Dose Monitoring Side-effects

Tacrolimus 0·05–0·1 mg/kg in two divided doses
orally; trough 4–8 ng/mL
Ciclosporin 4–6 mg/kg per day in two divided doses
orally; trough 80–150 ng/mL
Mycophenolate 600 mg/m² in two divided doses orally;
mofetil* maximum dose 1200 mg/m²
Cyclophosphamide† 500–750 mg/m² intravenously every month
for 6 months; coadministration with sodium
mercaptoethane sulphonate, and
ondansetron
Rituximab* 375–750 mg/m² (maximum 1000 mg)
intravenously; 2–4 infusions, 1–2 weeks apart full blood count
Enalapril and 0·2–0·5 mg/kg per day for enalapril
ramipril and 1·25–6 mg/m² per day for ramipril
Drug concentrations, creatinine
electrolytes, glucose,
transaminases
Drug concentrations, creatinine
electrolytes, glucose,
transaminases
Area under the curve
measurements, full blood counts,
creatinine, transaminases
Blood counts
Hepatitis B screen, CD19 count,
Creatinine, electrolytes, caution if
hypovolaemia or hypotension
Nephrotoxicity, hypertension, hyperglycaemia,
seizures, diarrhoea, hypomagnesemia
Nephrotoxicity, hypertension, hypertrichosis,
gingival hyperplasia
Abdominal pain, diarrhoea, anorexia. Leucopenia
and raised transaminases are uncommon
Alopecia, marrow suppression, vomiting,
haemorrhagic cystitis, risk of systemic infections.
Long-term risks: cancer, infertility
Monitoring of allergic reactions during infusion,
immunosuppression, risk of infections
Dry cough, hyperkalaemia, hypotension, anaemia,
nephrotoxicity

Drugs options are combined with alternate day prednisolone: 1·5 mg/kg on alternate days for 2–4 weeks, 1·25 mg/kg in the subsequent 2–4 weeks, 1 mg/kg for 3 months,
and 0·5–0·75 mg/kg for 9–12 months. *Scarce evidence for efficacy of these drugs. †Oral cyclophosphamide is not recommended for steroid resistance. Intravenous
cyclophosphamide limited to centres where cost is a major factor.

Table 1: Available drug options for the treatment of steroid-resistant nephrotic syndrome

cyto­skeleton has been suggested.20 Several prospective
studies have been done with calcineurin inhibitors for
patients with SRNS. Treatment with ciclosporin has been
shown to be effective in inducing complete or partial
remission in placebo-controlled studies, and in com­
parison with intravenous cyclo­ phosph­ amide.21 A
randomised controlled trial of 131 children with SRNS
compared the efficacy of 12-month treatment with
tacrolimus with six intravenous pulses of cyclo­phosph­
amide.22 Complete remission was reported in 33 of 63
(52%) patients receiving tacrolimus and in 9 of 51 (18%)
patients receiving cyclophosphamide. Respective partial
res­ponses were 19 of 63 (30%) and 19 of 61 (31%).
Another trial, funded by the US National Institutes of
Health (NIH), showed a 46% combined complete and
partial response with ciclosporin.18
The probability of complete or partial response to
treatment with calcineurin inhibitors is similar in
patients with minimal change disease (46·5%),
mesangio­­­­proliferative glomerulonephritis (38·0%), and
FSGS (39·0%).4,19 Although most patients with SRNS
who respond to treatment stay in remission, relapses are
not uncommon. Most of these relapses respond to
addition of daily corticosteroid treatment (table 1).
Therapies with tacrolimus and ciclosporin show similar
efficacy.23 Treatment with tacrolimus might be preferred
because of lower risk of relapses and fewer side-effects.24
12 hour trough levels are used for monitoring treatment
with ciclosporin and tacrolimus; target levels vary between
80–150 ng/mL for ciclosporin and 4–8 ng/mL for
tacrolimus.24–26 Calcineurin inhibitors are metabolised by
cytochrome P450 enzymes (CYP3A). Therefore, their
concentrations are affected by inhibitors or inducers of
this pathway, resulting in increased or reduced amounts
of cytochrome P450, respectively. The main CYP3A
inhibitors are azoles (fluconazole, ketoconazole, and
voriconazole), calcium channel blockers (diltiazem
hydrochloride and verapamil hydrochloride), protease
inhibitors (ritonavir, saquinavir, and indinavir sulphate),
macrolides (clarithromycin and erythromycin), and grape­
fruit and pomegranate juices. Clinically effective inducers
of the enzymatic pathway are rifampicin, rifabutin,
phenytoin, phenobarbital, and some non-nucleoside
reverse transcriptase inhibitors (efavirenz and nevirapine).
Therapeutic monitoring of calcineurin inhibitor concen­
tration is necessary in patients receiving concomitant
treatment with these drugs.
The most important side-effect of calcineurin inhibitors
is the potential risk on long-term renal function.
Although the medical community has not reached a
consensus on the duration of treatment, most experts
consider weaning off calcineurin inhibitors after
2–3 years.2,27 The risk of relapse on stopping treatment is
high, but some children can be weaned off the medication
and maintain remission. Treatment with a calcineurin
inhibitor increases the risk of acute kidney injury,
particularly if the child is depleted intravascularly.
Temporary discontinuation of treatment could be
considered during such episodes. Cosmetic side-effects,
including hypertrichosis and gingival hyperplasia,
are common with ciclosporin. Glucose intolerance and
diarrhoea are potential risks with tacrolimus. Both
medications have a small risk of neurotoxicity, mani­
festing with headache and occasional seizures.
Mycophenolate mofetil
Mycophenolate mofetil, which works by selective in­
hibition of DNA replication in T and B lymphocytes, is

4 www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9


considered less effective than calcineurin inhibitors.23,26
However, an NIH trial in children and adults (<40 years of
age) with steroid-resistant FSGS did not show a statistically
significant difference in treatment response between the
combination of oral dexamethasone and mycophenolate
mofetil compared with ciclosporin.18 A report by Sinha
and colleagues26 showed that an early switch (at 6 months)
from tacrolimus to mycophenolate mofetil was not
effective in sustaining remission in patients with SRNS.
Studies in paediatric transplant recipients suggest the
importance of measuring area under the curve
(mycophenolic acid concentration over time) for
monitoring treatment with mycophenolate mofetil.28 The
proposed area under the curve measurement for patients
with steroid-sensitive nephrotic syndrome is between
30 mg/h per litre and 60 mg/h per litre.29 Information on
target blood concentrations of myco­phenolate mofetil for
patients with SRNS is scarce, and possibly targeting
higher concentrations than those currently in clinical
practice might be associated with better response to
mycophenolate mofetil treatment. The side-effect profile
of mycophenolate mofetil makes it preferable to
calcineurin inhibitors, since mycophenolate mofetil does
not have adverse effects on renal function. Gastro­
intestinal disturbances are important; leucopenia and
other adverse effects are less common.
Patients who do not show remission following treat­
ment with calcineurin inhibitors pose a great challenge
for management of SRNS. Few reports suggest that the
combined use of calcineurin inhibitors, mycophenolate
mofetil, and prednisone might be effective in inducing
partial or complete remission in a small proportion
of these patients.30,31 However, the intense immuno­
suppression associated with combined treatment could
predispose patients to serious infectious complications.
Cyclophosphamide
Cyclophosphamide, an alkylating agent, has been widely
used in patients with steroid-sensitive nephrotic syn­
drome. Early studies in SRNS did not show benefit with
use of oral cyclophosphamide and steroids com­ pared
with treatment with steroids only.32,33 Therefore, oral
cyclo­
phosphamide is not recommended for manage­
ment of SRNS.2,26
An aggressive regime, proposed by Tune and Mendoza,34
combined multiple pulses of intravenous methylpredni­
solone (30 mg/kg per dose, initially given every other day,
and then tapered to weekly and monthly dosing), oral
prednisone (2 mg/kg every other day), and oral cyclo­
phosph­amide. The efficacy of this protocol was variable,
with remission varying from 20–50%. These regimens
have substantial adverse events and are not recommended.
Intravenous cyclophosphamide is more effective than
oral treatment,35 and due to its low cost is still used in
resource-limited countries. Treatment involves six-dose
treatment with intravenous cyclophosphamide (once a
month) and tapering alternate day prednisolone,
www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9 5
Review
especially in patients with minimal change disease.19 A
review of data from multiple case series shows that
treatment with intravenous cyclophosphamide results in
complete and partial remission in 30–35% of patients.22,27
Cyclophosphamide can result in severe side-effects,
including haemorrhagic cystitis, bone marrow depres­
sion with leucopenia, and alopecia. The risk of azo­
ospermia is higher in pubertal than pre-pubertal boys
and is related to cumulative exposure to the drug; the risk
of female infertility is lower than for male patients.36 The
dose of intravenous cyclophosphamide used for SRNS is
considerably lower than that associated with infertility.
Rituximab
Rituximab, a monoclonal anti-CD20 antibody, is standard
treatment for children with frequently relapsing or
steroid-dependent nephrotic syndrome, particularly
when other immunosuppressive drugs have not achieved
longstanding full remission.37–39 Apart from action on
lymphocytes, rituximab might have off-target effects
on lipid metabolism in podocytes by binding to
sphingomyelin phosphodiesterase acid-like 3b protein
and regulating acid sphingomyelinase activity. The first
children with SRNS to be treated with rituximab were
reported by Bagga and colleagues,37 in 2007. Three patients
had a complete response and two had a partial response.
Further case series confirmed these findings, but the
overall response to treatment was less impressive.39,40 An
international cohort of 27 children showed response in
18 patients (67%), but only six patients had complete
response.41 Similar figures were found in other reports,
with complete remission in 27% and 29% of patients.25,42
The first, and to our knowledge only, randomised,
controlled study in children with SRNS included
31 patients who were non-responsive to calcineurin
inhibitors and steroids. All patients continued pred­
nisolone and the calcineurin inhibitors, whereas 16 also
received two doses (375 mg/m²) of rituximab. No
statistically significant reduction of proteinuria was
measured at 3 months.43 Despite limitations, many
paediatric nephrology centres use intravenous rituximab
in selected patients of steroid and calcineurin inhibitors-
resistant nephrotic syndrome. The dose and frequency
of administration is not defined. A range of doses
from 375 mg/m² (single dose) to 750 mg/m² per dose
(two doses given 7–14 days apart) are used.44
Rituximab is well tolerated but might cause infusion
reactions of varying severity.45 These reactions can be
controlled by premedication with steroids and anti­
histamines, and reduced rate of infusion. Bone marrow
suppression with neutropenia has been described.46
The risks for prolonged hypogamma­globulinaemia are
controversial and, although monitoring blood concen­
tration of immunoglobulins has been suggested, most
centres do not administer intravenous immunoglobulins,
even if they find low immunoglobulin concentrations in
the blood.47
 Review
Trial Study design and indication
NCT02592798 Safety and efficacy of abatacept (every 28 days Phase 2 placebo-controlled; minimal
for four cycles) in steroid-resistant and change disease, FSGS
calcineurin-resistant illness (adults and
children 6–17 years)
NCT02394106 Ofatumumab in steroid-resistant and Phase 2, double-blind, placebo-controlled;
calcineurin inhibitor-resistant nephrotic minimal change disease, FSGS,
syndrome (children 2–18 years) mesangioproliferative glomerulonephritis
NCT02382874 Adipose-derived mesenchymal stromal cells Phase 1 open label pilot study on safey
(children 2–14 years) and efficacy; multiresistant FSGS
NCT00098020 Efficacy of 6 months’ therapy with isotretinoin Phase 2 open label pilot study on safey
(children ≥16 years and adults) with resistant and efficacy; minimal change disease,
nephrotic syndrome FSGS, HIV-associated disease
FSGS=focal segmental glomerulosclerosis.
Table 2: Ongoing clinical trials of steroid-resistant nephrotic syndrome in children and adolescents
A small but increased risk of viral infections is present
after rituximab treatment. Cerebral infections with
JC virus have been described in adult patients and also
reactivation of hepatitis B.48,49 A severe respiratory illness,
rituximab-associated lung injury, develops in a very small
group of children.50 Infections with Pneumocystis jiroveci
have also been reported.51 Previous treatment can result
in antichimeric antibodies, which reduce the effect of
rituximab and might result in anaphylactic reactions.
Rituximab-induced depletion of CD19 B cells is taken
as a sign of effective treatment and usually lasts for
6–8 months.52 Data from most studies suggest that
relapses of nephrotic syndrome are uncommon in
patients with B lymphocyte depletion. Therapeutic
response does, however, last several months, even after
repopulation of B cells.42 Recent data also suggest that
recovery of memory B cells might predict the occurrence
of a relapse.53
Although treatment with calcineurin inhibitors is
effective in most patients with SRNS, the precise duration
of treatment is not defined. Also, a few patients continue to
relapse while on treatment with calcineurin inhibitors and
show features of steroid or calcineurin inhibitor toxicity.
Treatment with two doses of rituximab has been shown to
enable weaning off treatment with calcineurin inhibitors
and prednisolone. A report from Ito and colleagues39
showed that treatment with rituximab resulted in a
71% reduction in relapse, with withdrawal of calcineurin
inhibitors in 95% and corticosteroids in 74% patients.
More information is required regarding the frequency of
redosing and potential long-term toxicities.
Other treatments
The treatment of steroid-resistant and calcineurin
inhibitor-resistant nephrotic syndrome is challenging.
Newer drugs are available that target immune-mediated
inflammation and glomerular damage (ofatumumab,
adrenocorticotropic hormone, abatacept, adalimumab,
and saquinavir); inhibit action of permeability factors
(galactose and inhibitors of soluble urokinase receptor);
6 www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9
or prevent glomerular fibrosis (inhibitors of transforming
growth factor β, fresoli­mumab, microRNA, pirfenidone,
rosiglitazone, pioglita­zone hydrochloride, and paclitaxel).54
Some of these strategies are being examined
prospectively in phase 1–4 studies (table 2). However,
none of these drugs are currently recommended for
treatment of patients with SRNS.
Ofatumumab
The first use of ofatumumab, a humanised anti-CD20
monoclonal antibody, was reported in five children who
were resistant to cyclophosphamide, mycophenolate
mofetil, calcineurin inhibitors, and rituximab.55 The
results were exceptionally positive with all patients going
into remission with normal blood concentration of
albumin 6-weeks after treatment. Two other studies that
reported on nine children have shown that four patients
achieved complete remission, two had partial remission,
two did not respond, and one patient had a severe
infusion reaction.56,57
Abatacept
Abatacept (cytotoxic T lymphocyte-associated antigen
4-immunoglobulin fusion protein, CTLA-4-Ig) is a co-
stimulation inhibitor targeting B7–1 (CD80) on antigen-
presenting cells, including podocytes. In 2013, treatment
with this drug was reported to induce partial or total
remission in four patients with recurrent and one with
primary FSGS.58 The authors also showed that abatacept
stabilises β1-integrin activation in podocytes in vitro,
reducing proteinuria in patients with B7–1-positive
glomerular disease. These findings have not been
replicated in other patients treated with abatacept or with
belatacept, a drug that binds B7–1 with even higher
affinity than abatacept.59,60
Adrenocorticotropic hormone
Administration of adrenocorticotropic hormone was one
of the first therapies for nephrotic syndrome.61 Since
clinical and experimental evidence suggested that
adrenocorticotropic hormone has antiproteinuric, lipid-
lowering, and renoprotective properties,62 the drug was
reintroduced as treatment for nephrotic syndrome.
Hogan and colleagues63 treated 24 adult patients with
steroid-resistant or steroid-dependent FSGS with adreno­
corticotropic hormone and achieved remission in seven
(29%) patients. Adrenocorticotropic hormone is proposed
to have actions beyond those of corticosteroids via anti-
inflammatory mechanisms, or directly on podocytes via
the melanocortin receptor.62,64
Adalimumab
Since tumour necrosis factor is upregulated in human
and experimental models of FSGS, monoclonal
antibodies have been used to inhibit this pathway.65 In a
phase 1 trial on novel therapies for resistant FSGS
(FONT), adalimumab was well tolerated, and after

16 months of follow-up, four of ten patients showed
stable kidney function and reduced proteinuria.66 Studies
are required to confirm the benefits of adalimumab in
slowing the progression of FSGS.
Lipoprotein apheresis
11 children with steroid-resistant and ciclosporin-
resistant nephrotic syndrome were treated with
lipoprotein apheresis three times per week, for 3 weeks,
and then once a week for 6 weeks. Prednisone was given
at a dose of 1 mg/kg per day during the last 6 weeks and
then tapered.67 Five of these children had complete
remission and two had partial remission. Those children
with complete response showed normal kidney function
during a median follow-up of 4·4 (range 4·0–11·1) years,
whereas patients with partial and no response progressed
to end-stage renal failure. Further studies are ongoing to
determine the efficacy of this treatment.
Symptomatic treatment
A comprehensive review on symptomatic treatments for
children with SNRS was published in 2016.68
Oedema
Oedema is a cardinal feature of nephrotic syndrome and
often a debilitating symptom. A bodyweight increase by
25% from the baseline (before treatment) is not unusual
in children with nephrotic syndrome. However, a
relatively large group of children show only mild oedema,
despite having chronically low concentrations of serum
albumin, sometimes below 10 g/L.
Initial treatment consists of restriction of intake of
sodium and of fluids to two-thirds of maintenance.69
Careful use of diuretics including furosemide, meto­
lazone, and spironolactone is helpful.70 Many children with
active nephrotic syndrome have a loss of fluid from the
vascular compartment to the extracellular space and have
low intravascular volume. Aggressive diuretic treatment in
these patients carries a risk of hypovolaemia and acute
kidney injury.71 Despite conservative management, a small
group of children continue to have substantial oedema
resulting in discomfort. These children need repeated
infusions of human albumin together with intravenous
furosemide.
Residual proteinuria
Children with SRNS who show partial or no response to
calcineurin inhibitors continue to show proteinuria.
Studies in adults, as well as children, show that treatment
with angiotensin-converting enzyme (ACE) inhibitors
reduces the degree of proteinuria by 30–40% in a
dose-dependent and time-dependent manner and,
thus, is recommended.72,73 Angiotensin receptor blockers
(valsartan and irbesartan) are advised for patients
showing adverse effects to ACE inhibitors, mainly cough.
Combined treatment with an ACE inhibitor and
angiotensin receptor blocker results in further reduction
www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9 7
Review
of proteinuria by approximately 15%. However, patients
receiving dual treatment are at risk of hypotension,
hyperkalaemia, and impaired kidney function; therefore,
the combination is not recommended.74 The DUET
study,75 which concluded in 2017, showed that sparsentan,
a novel drug with dual blockade of the angiotensin II
receptor and endothelin 1, was more efficient than
irbesartan in decreasing proteinuria in SRNS.
Infection prophylaxis
Children with SRNS have increased risk of infections,
due to urinary loss of immunoglobulins and effect of
immunosuppressive treatment. An important compli­
cation is spontaneous bacterial peritonitis, often caused
by Streptococcus pneumoniae or by gram-negative bacteria.
Although few paediatric nephrology centres advocate the
use of prophylactic oral penicillin, most do not follow
this practice.68 All patients with SRNS should receive the
pneumococcal vaccine.
Viral infections, especially varicella zoster virus, can be
a serious problem in immunocompromised patients.68 If
a child has substantial exposure to chickenpox (within
the preceding 48 h of appearance of rash), immunity
against varicella should be checked. If not immune,
varicella zoster immunoglobulin is given as soon as
possible, but up to 10 days after exposure. Confirmed
chickenpox while on prednisolone or immunosuppressive
treatment, or within 3 months of stopping, should be
treated with acyclovir for 7 days. Intravenous treatment is
considered in all patients, especially if unwell, and
usually for at least the first 48 h of treatment.
Thrombosis
Children with ongoing nephrotic syndrome have an
increased risk of both venous and arterial thrombosis.
Prophylactic aspirin is advised, but is not widely used.68
Physicians should have a high index of suspicion for
thrombosis. Prompt evaluation and treatment with
heparin followed by oral anticoagulants is recommended.
Hyperlipidaemia
Patients with SRNS often show markedly raised blood
concentrations of cholesterol and triglycerides.76 The
abnormal lipid profile might contribute to later
cardiovascular morbidity. Adult patients with nephrotic
syndrome are treated with statins, with satisfactory
improvement of lipid concentrations. Treatment with
statins is not routinely used in children with SRNS and
prospective studies are required.77
Vitamin D
Children with SRNS have urinary losses of
vitamin D-binding protein, which might lead to reduced
bone density and increased risk of fractures. A study on
supplementation with vitamin D and calcium did not
show any benefits on bone mineral density, but did show
an increase in the risk of hypercalciuria.78
 Review
Panel 2: Prevention and management of recurrent focal segmental
glomerulosclerosis after kidney transplantation
Prevention of recurrence
• Ensure period of normalised serum albumin before transplantation
• Genetic screening of recipient if living-related donor
• Intravenous rituximab (375 mg/m²; one or two doses) 2 weeks before transplantation
• Plasma exchanges (begin 7–10 days before transplantation)
• Induction with intravenous methylprednisolone and basiliximab;
triple immunosuppression
• Post-transplantation proteinuria screen: daily for 1 week; weekly for 4 weeks;
every 3 months for first year; and every 6 months thereafter
Treatments for recurrence
• Plasma exchange (8–12 sessions for response; might require long-term for maintenance
of remission; 1–1·5 volume exchanges) on alternate days for 7–10 sessions, then taper
and continue until proteinuria subsides
• Methylprednisolone (10–15 mg/kg intravenously, three doses daily)
• Switch to high-dose ciclosporin, targeting trough concentrations of 250–300 ng/mL
for 2–3 weeks; alternatively, continue tacrolimus at higher dose
• Rituximab (1–6 doses used; early use and normal serum albumin at onset predict
response): 375 mg/m², two doses 1 week apart; avoid plasma exchange for 36 h
following treatment; monitor CD19 depletion
• Other treatments (considered for refractory patients; variable efficacy): low-density
lipoprotein apheresis, and oral cyclophosphamide (8–12 weeks) to replace
mycophenolate mofetil.
Thyroid disease
Children with SRNS, especially congenital nephrotic
syndrome, lose large amounts of thyroid-binding protein
in urine. Therefore, the amount of thyroid hormones in
such patients should be monitored.68
Prognosis
Children with SRNS are at risk of progressing to end-
stage kidney disease. One study showed renal survival at
10 years to vary between 54·6% and 100%, depending on
renal histology and treatment. Important influencing
factors for unsatisfactory outcome were a proven genetic
cause, renal histology, response to immunosuppressive
treat­ment, and duration of follow-up.79 Data from a large
multicentre registry showed that 10-year survival free of
end-stage kidney disease was 29% in patients with a
genetic diagnosis, 52% in those with FSGS, and 79% in
minimal change disease.19 The 10-year renal survival
in the group that responded to immunosuppression
was 94%, compared with 72% with partial remission, and
43% with non-response to treatment.19
Recurrence in transplantation
Several paediatric nephrology centres advocate nephrect­
omy before accepting the child for trans­plantation. This
procedure is used to reduce the problems related to
continuous proteinuria, which can make the monitoring
of any recurrence of the disease in the transplanted
kidney easier.
8 www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9
Results from various case series show that almost
30–50% patients with idiopathic SRNS with end-stage
kidney disease who receive an allograft can develop
recurrent FSGS. Patients with recurrent FSGS are at risk
of delayed graft function and graft loss, approaching
30–50% at 5 years.80 Although the pathogenesis is
unclear, disease recurrence is attributed to circulating
permeability factors. Recurrent proteinuria occurs from
hours to days after the transplant, and is associated with
progressive hypoalbuminaemia and effacement of
podocyte foot process under electron microscopy.
Features associated with increased risk of recurrent
FSGS include onset of disease before 15 years of age,
non-genetic (immune) form of the disease, mesangial
proliferation on renal biopsy, and rapid progression to
end-stage kidney disease.81,82
A report on 150 patients with nephrotic syndrome who
underwent renal transplantation showed that the risk of
recurrence was highest (26 of 28, 93%) in patients who
were initially corticosteroid responsive, but showed late
resistance; intermediate (26 of 86, 30%) in those with
initial resistance, but no known mutations; and none in
those with mutations affecting key podocyte genes.83 A
panel of antibodies against seven glomerular antigens
(CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and
APOL2) is reported to predict post-transplant FSGS
recurrence with 92% accuracy; findings of this report
need confirmation.84
Treatment recommendations
All patients with FSGS who are about to undergo renal
transplantation should be advised about the possibility of
recurrence of disease. Combined treatment with
1–2 doses of rituximab and pretransplant plasmapheresis
is likely to benefit recipients at high risk of recurrent
FSGS. Since rituximab is cleared from the body by
plasma exchange, an interval of 36–48 h between rituxi­
mab infusion and the exchange is recommended.85
Strategies for management of children with docu­
mented recurrent disease are not based on randomised
trials, but on observational reports and clinical expertise.
Typically plasma exchange or immunoadsorption in
combination with high-dose ciclosporin (trough concen­
trations 250–300 ng/mL for 3 weeks) and cyclophos­
phamide (2–2·5 mg/kg per day for 3 months) is used.
With these strategies, 70% of children with recurrent
FSGS achieve complete or partial remission.86,87 Experts
have reported remission of proteinuria in 64% patients
with the use of rituximab (2–6 doses of 375 mg/m²,
administered once every 1–2 weeks), in conjunction with
plasma exchange and post-trans­ plantation immuno­
suppression.88 The median time to best clinical response
was 2 months (range 0·6–12·0 months). On stepwise
regression, normal serum albumin concentration at
recurrence (suggesting mild FSGS) and young age
predict a favourable response to treatment.88 In a review
on patients with recurrent FSGS treated with rituximab

Search strategy and selection criteria
We did multiple searches on PubMed and Cochrane over the
past 10 years for studies published until Jan 1, 2018, with
different combinations of the search terms “nephrotic
syndrome”, “steroid resistant treatment”, “calcineurin
inhibitor”, “ciclosporin”, “tacrolimus”, “mycophenolate
mofetil”, “rituximab”, “outcome”, “prognosis”, “kidney
transplantation”, and “relapse after transplantation”. Studies
were chosen based on the quality and amount of information.
Only studies published in Eglish were used.
infusions and plasma exchange, the 12 patients who
achieved remission had received the infusions statistically
significantly earlier than the 13 patients who did not
respond (mean 100·5 days [SD 95·4] from onset of
recurrence vs 468·1 days [379·8]).89 A systematic review of
423 patients with recurrent FSGS showed that patients
treated with prompt plasma exchanges within 2 weeks of
recurrence show likelihood of remission.86 The role of
lipid apheresis in achieving remission in patients with
recurrent FSGS is under investigation. Guidelines for
prevention and management of recurrent FSGS in
allograft recipients are summarised in panel 2.
Future directions in research
The biggest challenge, as we see it, is to define the
presumed circulating factors that cause the disease in
most patients with SRNS. The nature of this factor has
been investigated for several decades without success.
The precise effect of this circulating factor on podocyte
biology also needs to be clarified. We suspect that the
circulating factor is in some way related to the immune
system, since all currently effective treatments are with
immunosuppressive medications.
The number of genes causing SRNS will undoubtedly
continue to rise until all have been found. Patients with
SRNS who have an underlying genetic disorder are
unlikely to respond to medications and might be future
candidates for genetic therapy, including genomic
editing.
Contributors
All authors wrote the first draft of one part of the Review. The draft was
reviewed by all authors iteratively, until all three approved of the final
manuscript.
Declaration of interests
We declare no competing interests.
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