Improving prediction of disease outcomes and treatment options in
childhood steroid-resistant nephrotic syndrome
Dr Ethan Sen
Clinical Research Fellow and Specialty Registrar in Paediatrics
Bristol Renal, University of Bristol
Normally your kidneys work like a specialised sieve to
filter out small waste products while keeping larger
substances, like proteins, in your blood. If your kidneys
become leaky, proteins pass into your urine and fluid
builds up in the wrong places in your body. This leads
to swelling of your face and other areas. This is called
nephrotic syndrome and is a disease mainly affecting
children.1 Standard treatment is with steroids and
although they work in most children, for about one in
five they do not. This is known as steroid-resistant
nephrotic syndrome (SRNS). Among this group, many
patients develop kidney failure needing dialysis and
eventually a transplant. Unfortunately, in some children
the disease comes back in the new kidney after a
transplant.
We know from previous research that in nephrotic
syndrome the normal shape of specialised kidney cells,
called podocytes, is disrupted. This leads to breakdown
of the sieve-like barrier and loss of protein in the urine
(Figure 1).2
SRNS has several different causes. In about one third
of patients it is a genetic disease. In these cases it is
caused by defects (mutations) in one of more than 30
genes which control how podocytes work.4 In the other
cases, the cause of disease is unknown but it may
involve proteins released into the patient’s blood from
cells of their immune system.
Testing for genetic mutations and measuring levels of
proteins in blood could help to separate patients with
SRNS into groups which respond differently to
treatment. Characteristics, such as genes or proteins,
that can be measured and linked with disease are called
biomarkers. Journal articles have highlighted that the
development of biomarkers will be important for
improved treatment of kidney diseases.5
Figures
Results
Figure 1: The kidney filter with normal podocytes (left) and
disrupted podocytes (right)
The kidney filter has three parts: (1) Podocytes sit next to the urine and are linked together by slit diaphragms
(SD). (2) The glomerular basement membrane (GBM) is a meshwork which supports the cells. (3) Endothelial
cells sit next to the blood. Normally red blood cells (rbc) and proteins like albumin stay inside the blood (left
picture). In nephrotic syndrome, albumin leaks into urine (right picture). Adapted from: Ronco P. (2007)3
Figure 2: Age of disease onset in SRNS patients with or without
causative genetic mutations (total number = 188)
60
Number of patients
Background
No mutations
50
With mutations
Figure 2: Most children with SRNS that starts under
3 months of age have genetic disease. We did find a
genetic cause in some children of all ages. A
European study of children with SRNS has shown a
similar age distribution.8
Figure 3: Almost a third of children needed a
transplant and disease recurred in almost a third of
these. Among 48 patients with genetic disease, 50%
had a transplant. In 140 patients with no genetic
cause, only 22% needed a transplant.
Figure 4: We looked at different patterns of steroid
resistance (SR). Primary SR means the children
never responded to steroid treatment. Secondary
SR means that they did improve in the first four
weeks of steroids but later became resistant.
Presumed SR means the children were not given
steroids usually because they had nephrotic
syndrome from birth.
We found that secondary SR is most strongly
predictive of disease recurrence after a transplant.
Our key findings from the UK are similar to results
from international studies8:
• A higher rate of transplantation in patients with
genetic disease or presumed SR. But these
groups have low risk of recurrence after
transplant.
• A similar rate of transplantation in primary and
secondary SR. But children with secondary SR
have a doubled risk of recurrence.
40
We found that between May 2013 and July 2015,
doctors requested the SRNS gene test for 302
patients in the UK and 11 other countries. Of these,
209 were children with SRNS and just over one in
five (20.6%) had a genetic cause. We identified 31
patients with new mutations which had not previously
been published.
30
20
10
0
0-0.25 0.25-1
1-3
3-5
5-7
7-9
9-11 11-13 13-15 15-17
Age of disease onset (years)
Future Directions
Our Research Questions
• Can we identify early in the disease which
patients will progress to kidney failure,
transplant and recurrence?
• Which patients respond to which treatments?
• What biomarkers may help with predicting
this?
• Can we develop a treatment pathway based
on clinical features, genetics and blood tests?
Methods
Figure 3: Transplantation and subsequent recurrence in SRNS
patients (total number = 188)
60
Number of patients
At the moment we do not have good ways to
predict which children with SRNS will develop
kidney failure and which will respond to particular
treatments. If we could identify high-risk and lowrisk patients we could better target therapy and
take actions to minimise the chance of disease
recurrence after transplant. The important
research questions are:
Transplant
50
40
30
20
10
0
0-0.25 0.25-1
Transplant
Yes
No
Total
Number
55
133
188
1-3
3-5
5-7
7-9
9-11 11-13 13-15 15-17
Age of disease onset (years)
• So far we have analysed over 180 patients to see if
they have genetic disease. We checked all their
genes in a process called whole exome sequencing.
We also looked at whether they progressed to need
a transplant and had recurrence of disease
afterwards.
• We have used previous research from our group6 to
develop a test of 37 genes thought to cause SRNS7.
Since May 2013, this test has been available through
the NHS Genetics Service at Bristol Genetics
Laboratory. We have looked at the results from
patients tested between May 2013 and July 2015 to
see how many have a genetic disease.
References
All 15 who
suffered
recurrence had
non-genetic
SRNS
Percentage (%)
29.3
70.7
100.0
Recurrence Total Percentage (%)
Yes
15
27.3
No
40
72.7
Total
55
100.0
• The UK National Registry for Rare Kidney Diseases
(RaDaR): Since 2010 we have collected data about
patients with a range of kidney diseases. Initially we
focused on children with SRNS but have now
expanded to include adults and those with steroidsensitive nephrotic syndrome.
• The National Study of Nephrotic Syndrome
(NephroS): We have collected blood samples from
patients for genetic (DNA) testing to look for known
and new genes that cause SRNS.
No Transplant
Figure 4: Outcomes after transplant according to type of
steroid resistance (SR) (total number = 184)
Presumed SR
Total number
25
Transplant
14
Recurrence
0
No recurrence
14
Primary SR
Total number
129
Transplant
33
Recurrence
10
No recurrence
23
56%
0.0%
100%
25.6%
30.3%
69.7%
Type of steroid resistance (total number = 184)
Secondary SR
Total number
30
Transplant
8
Recurrence
5
No recurrence
3
26.7%
62.5%
37.5%
Primary
Secondary
Our research is ongoing and we now have over
1300 patients with nephrotic syndrome recruited
into RaDaR. Our current projects are:
• To look at responses to drug treatments other
than steroids. We will compare patients with and
without mutations and with different patterns of
steroid resistance.
• To carry out more detailed genetic testing using
whole genome sequencing (looking at all a
patient’s DNA).
• To measure levels of proteins in patients’
plasma (the liquid part of blood).
We will
compare times when patients have active
disease and when it is well controlled. We hope
to identify biomarkers that can help with
treatment.
Presumed
Acknowledgements: PhD Supervisors at Bristol Renal: Professor Moin Saleem & Dr Gavin Welsh. Collaborators at Bristol Renal: Agnieszka Bierzynska,
Elizabeth Colby, Dan Henson, Maryam Afzal. Collaborators at Bristol Genetics Laboratory, North Bristol NHS Trust: Philip Dean, Laura Yarram-Smith, Maggie
Williams.
1. Krishnan RG. Nephrotic syndrome. Paediatrics & Child Health.
2012;22:337-340.
2. Kaneko K et al. Pathogenesis of childhood idiopathic nephrotic
syndrome: a paradigm shift from T-cells to podocytes. World J
Pediatr. 2015;11:21-8.
3. Ronco P. Proteinuria: is it all in the foot? J Clin Invest.
2007;117:2079–2082.
4. Bierzynska A et al. Genes and podocytes - new insights into
mechanisms of podocytopathy. Front Endocrinol (Lausanne).
2015;5:226.
5. Mariani LH, Kretzler M. Pro: 'The usefulness of biomarkers in
glomerular diseases'. The problem: moving from syndrome to
mechanism--individual patient variability in disease presentation,
course and response to therapy. Nephrol Dial Transplant.
2015;30:892-8.
6. McCarthy HJ et al. Simultaneous sequencing of 24 genes
associated with steroid-resistant nephrotic syndrome. Clin J Am Soc
Nephrol. 2013;8:637-48.
7. Bristol Genetics Laboratory. SRNS gene panel test. Available at:
https://www.nbt.nhs.uk/sites/default/files/filemanager/editor/BGL%20
service%20proforma%20for%20Nephrotic%20Syndrome.pdf
8. Trautmann A et al. Spectrum of steroid-resistant and congenital
nephrotic syndrome in children: the PodoNet registry cohort. Clin J
Am Soc Nephrol. 2015;10:592-600.
Funding
Dr Ethan Sen is funded by a NIHR Rare Diseases
Translational Research Collaboration (RD-TRC)
Clinical Research Fellowship. The views expressed
are those of the author and not necessarily those of
the NHS, the NIHR or the Department of Health.
RaDaR and NephroS have received funding from the
NIHR RD-TRC, Medical Research Council, Kidney
Research UK, British Kidney Patient Association,
NephCure Kidney International and Kids Kidney
Research.