Download Efficacy and safety of rituximab treatment in children with primary

ORIGINAL ARTICLE
JNEPHROL 2012; 25 ( 06 ) : 1060 -1066
DOI: 10.5301/jn.5000096
Efficacy and safety of rituximab treatment
in children with primary glomerulonephritis
Jacek Zachwieja, Magdalena Silska,
Danuta Ostalska-Nowicka, Jolanta Soltysiak,
Katarzyna Lipkowska, Andrzej Blumczynski,
Anna Musielak
Introduction
Abstract
Background: The aim of our study was to analyze the
efficacy and safety of rituximab, a chimeric monoclonal antibody against CD20 lymphocytes, as a nonstandard immunosuppressive therapy in children with different types of primary glomerulonephritis who were
not eligible for routine treatment.
Methods: The study group was composed of 16 children with proteinuric glomerulopathies, not responding to standard immunosuppressive therapy. The indications included steroid-resistant nephrotic syndrome
(n=14) and steroid-dependent nephrotic syndrome
(n=2). The dose of rituximab was established as 375
mg/m2 of body surface area, administered by intravenous infusion once weekly for 1 to 4 weeks, depending
on the CD19 lymphocyte count. We evaluated proteinuria and plasma concentration of CD19 lymphocytes at
intervals of 1, 3 and 6 months, after which patients received a single repeat dose.
Results: Remission, defined as proteinuria less than
150 mg per 24 hours, was observed in 7 of the 16
children. There were no statistically significant differences in leukocyte counts between single and multiple
rituximab doses. We also did not observe any clinical
or biochemical side effects.
Conclusions: In conclusion, we postulate that alternative rituximab therapy should be taken into consideration in nephrotic patients not responding to standard
therapy.
Key words: Children, Nephrotic syndrome, Rituximab
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Department of Pediatric Nephrology, Poznan University of
Medical Science, Poznan - Poland
Glomerulonephritis, encompassing both the primary kidney disease and the consequent changes in the course of
systemic disease, is characterized by an inflammatory process leading to damage of the glomeruli. According to the
etiology as well as the clinical and microscopic picture, 8
main types of glomerulonephritis are distinguished. Secondary glomerulonephritis can be observed in systemic
lupus erythematosus, Henoch-Schönlein purpura, small
vessel disease, rheumatoid arthritis, in the course of infection, neoplastic changes or cirrhosis. The clinical manifestation of glomerulonephritis may be isolated proteinuria,
isolated erythrocyturia, proteinuria with erythrocyturia, nephritic syndrome or nephrotic syndrome as well as acute or
chronic kidney insufficiency.
The most common variant occurring in children is idiopathic
nephrotic syndrome with minimal changes in the kidney biopsy (1). Proteinuria, which is present in most cases of glomerulonephritis, is actually regarded as the crucial destructive factor for kidney structure. The inflammatory sequence
within the nephrons and renal parenchyma progresses to
end-stage renal disease with the necessity of renal replacement therapy (2). Among different types of secondary glomerulonephritis, the most hazardous cause in teenagers is
systemic lupus erythematosus nephropathy, which may be
associated with an unfavorable prognosis (3).
The main treatment strategy is based on immunosuppressive therapy and usually starts with glucocorticosteroids
(GCs). Although most children respond positively to GCs,
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2012; 25 ( 06 ) : 1060 -1066
in many cases, due to steroid resistance or steroid dependence, it is necessary to prolong prednisolone therapy or
introduce cyclophosphamide and/or calcineurin inhibitors
to induce and maintain complete remission (4). The reported toxicity and inadequate clinical response to this therapy
drive the search for more effective and safer treatments (57). Unfortunately, the clinical effectiveness of a still promising therapeutic alternative – mycophenolate mofetil – does
not lead to achievement of complete remission in nearly
half of patients (8).
Rituximab, a chimeric monoclonal antibody against the
protein CD20, which is primarily found on the surface of B
cells, has been used for the last decade as an immunosuppressive agent in such diseases as lymphomas, leukemias,
transplant rejection and some autoimmune disorders. Although the exact mechanism of its action is still unknown,
it may play a role in Ca2+ influx across plasma membranes,
maintaining intracellular Ca2+ concentration and especially
allowing activation of B cells. It primarily affects and entirely depletes peripheral B cells. Its cytotoxicity may occur
through complement-mediated lysis with direct apoptosis
induction or be based on antibody reaction (9). According
to some preliminary reports, rituximab can be used not
only in kidney transplantation but also as an alternative immunosuppressive therapy in primary and secondary glomerulonephritis (10). However, there are possible adverse
events observed in patients during rituximab therapy, such
as severe infusion reactions, cardiac arrest, infections, ),
hepatitis B reactivation and immune or pulmonary toxicity,
that can lead to disability or even death.
Aim of the study
In line with the above, the aim of our study was to analyze
the efficacy and safety of rituximab as an alternative immunosuppressive therapy in children with different types
of primary glomerulonephritis who were not eligible for the
standard treatment routine or dependent on this treatment.
Patients and methods
The study group was composed of 16 children with proteinuric glomerulopathies, not responding to standard immunosuppressive therapy, hospitalized between 2010 and
2011 in the Department of Pediatric Nephrology, Poznan
University of Medical Sciences in Poland. Five boys and
11 girls underwent a renal biopsy according to the recommendations of the International Study for Kidney Disease
in Children. These indications included steroid-resistant
nephrotic syndrome (SRNS, n=14) and steroid-dependent
nephrotic syndrome (SDNS, n=2). According to the World
Health Organization (WHO) definitions, histological evaluation of the study group revealed: minimal change disease
(MCD, n=3), diffuse mesangial proliferation (DMP, n=6),
membranoproliferative glomerulonephritis (MPGN, n=1),
glomerulosclerosis (GS, n=2), focal segmental glomerulosclerosis (FSGS, n=3) and extracapillary proliferative glomerulonephritis (EPGN, n=1).
Since rituximab is not yet approved for conventional therapy administered in different proteinuric glomerulonephropathies in Poland, we obtained the necessary approval from
the Polish Health Department, which authorized the use of
rituximab in this group of children. The study protocol was
ratified by the local ethics committee of Poznan University of Medical Sciences, and all of the parents of all of the
study participants gave written informed consent for the
investigation. The study was in accordance with the Declaration of Helsinki (11).
Treatment protocol
The dose of rituximab was established as 375 mg/m2 of
body surface area, administered by intravenous infusion
once weekly for 1 to 4 weeks, depending on the CD19
lymphocyte concentration. The rate of supply of the drug
initially was 50 ml/hour diluted in 500 mL of saline. In the
group of patients in whom there occurred severe side effects during rituximab supply, the infusion rate was reduced to 20 ml/hour. At a rate of 20 ml/hour of rituximab
supply further adverse events were not observed. During
the procedure, basic vital signs such as heart rate, blood
pressure and body temperature were monitored. The degree of proteinuria, number of leukocytes in the blood
stream and plasma concentration of CD19 lymphocytes at
intervals of 1, 3 and 6 months were evaluated, after which
patients received a single repeat dose of rituximab. During
treatment with rituximab the patients received co-trimoxazole prophylaxis for 3 months. To determine the number of CD19 lymphocytes, we used flow cytometry and
monoclonal antibodies. The patients during the treatment
were monitored for any side effects of the therapy. Therefore we assessed peripheral blood morphology and biochemical markers of potential renal or liver insufficiency.
In case of respiratory tract infection a control chest X-ray
was performed. The observation period ranged from 2 to
14 months, during which the patients continued to receive
therapy with calcineurin inhibitors, prednisolone or both.
Complete remission was defined as proteinuria less than
150 mg/24 hours, and partial remission as proteinuria less
than 25 mg/kg per 24 hours.
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
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Zachwieja et al: Efficacy and safety of rituximab
Control tests during treatment and assessment
of therapy safety
At the start of the treatment and after 1, 3 and 6 months,
relative to the initial state, a detailed assessment of biochemical parameters and clinical status of the patients was
conducted. We analyzed selected parameters including
blood pressure, peripheral blood morphology with particular emphasis on leukocyturia, creatinine serum concentration, glomerular filtration rate, electrolytes, lipid profile, aminotransferases, glycemia and of course daily proteinuria.
Every case of infection was monitored. Adverse reactions
occurring during rituximab infusion or in direct temporal association with it were subject to a special investigation. The
severity of side effects such as fever, chills, nausea and abdominal pain were transient and did not result in the need to
withdraw treatment.
Results
Table I summarizes the characteristics of the 16 studied patients, 5 boys and 11 girls aged 9-16, receiving rituximab
therapy. All underwent a renal biopsy. The indications included SRNS (n=14) and SDNS (n=2). According to the regimen,
most of the patients received medicaments such as prednisolone, methylprednisolone, cyclophosphamide, cyclosporin
A or mycophenolate mofetil prior to rituximab therapy.
Complete remission was observed in 7 of the 16 children after 6 months of observation. In patients who did not respond
to therapy, 7 children maintained partial remission with nonnephrotic proteinuria. Both of them had SRNS. On kidney
biopsy both presented diffuse mesangial proliferation. In
one case of a girl with SDNS and steroid-induced diabetes
mellitus, recurrence of nephrotic syndrome 7 months after
TABLE I
PROTEINURIA IN THE VARIOUS STAGES OF TREATMENT
Patient no.,
indication
for treatment
Number of
rituximab
pulses
Output proteinuria
(mg/kg per 24
hours) at start
of treatment
Proteinuria 1
month after
rituximab infusion
(mg/kg per 24
hours)
Proteinuria 3
months after
rituximab infusion
(mg/kg per 24
hours)
Proteinuria 6
months after
rituximab infusion
(mg/kg per 24
hours)
1. SRNS
4
0
0
0
11
2. SRNS
4
75
37
4
0
3. SDNS
4
0
0
0
0
4. SRNS
1
0
0
0
0
5. SRNS
1
15
5
15
19
6. SDNS
1
0
0
0
0
7. SRNS
1
5
0
0
249
8. SRNS
4
27
20
9.4
8
9. SRNS
1
5
0
5
8.4
10. SRNS
1
0
0
5
0
11. SRNS
1
10
0
15.8
13.2
13. SRNS
1
5
0
0
10
14. SRNS
1
15
0
4.3
7.1
15. SRNS
1
0
0
0
0
16. SRNS
1
30
20
15
15
SDNS = steroid-dependent nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome.
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the first rituximab infusion was observed. Histopathological
examination also showed DMP. In another case of a girl with
steroid-resistant and cyclosporine-dependent nephrotic
syndrome and DMP, acute renal failure developed which
required renal replacement therapy for 2 weeks, plasmapheresis and GC therapy. Currently the patient continues
treatment with cyclosporin A and remains in remission. Her
glomerular filtration rate stabilized at a level corresponding
to the second stage of chronic renal disease.
At the start of treatment, 6 patients were without proteinuria. Five of them maintained remission in the 6-month
observation period. In 1 patient with SRNS non-nephrotic
proteinuria was observed 6 months after the date of the primary rituximab dose. In the remaining 10 patients, non-nephrotic proteinuria was observed at baseline. In this group
steroid-resistant patients dominated. Most of them did not
manage to achieve permanent remission. Treatment failures were independent of age and sex of patients. Most of
them were children with SRNS.
Table II shows that under the influence of rituximab treatment, there were no changes in the average total leukocyte
count, which varied from 4.1345x10³ to 15.45x10³ after 1
month. There were also no statistically significant differences in leukocyte count when comparing single and multiple
rituximab doses.
In 14 patients after a single dose of rituximab, the number
of CD19 lymphocytes on flow cytometry was of the order of
0.0 (Tab. III). In the whole study group, the number was 0.0
after 1 month of observation, and in accordance with what
is known about rituximab metabolism, it increased again after 6 months, when the repeat dose was administered. With
the exception of flu-like reactions in half of the patients who
were administered the drug, we did not observe any important clinical or biochemical side effects requiring termination
of further drug administration, as monitored by blood morphology as well as plasma renal and liver markers.
TABLE II
TOTAL NUMBER OF LEUKOCYTES IN THE VARIOUS STAGES OF TREATMENT
Patient no., indication
for treatment
Rituximab number
of infusions
Leukocytes at
start of treatment
1 month
3 months
6 months
1. SRNS
4
9.28
11.58
8.14
8.43
2. SRNS
4
6.7
10.39
6.6
6.24
3. SDNS
4
12.6
6.47
5.5
8.48
4. SRNS
1
9.3
5.6
4.77
5.52
5. SRNS
1
5.81
6.43
7.06
7.00
6. SDNS
1
6.82
4.5
4.3
5.88
7. SRNS
1
5.32
4.6
3.42
5.1
8. SRNS
4
9.13
8.2
5.09
7.09
9. SRNS
1
15
9.5
5.5
6.2
10. SRNS
1
6.15
4.85
6.37
5.58
11. SRNS
1
3.79
9.6
8.6
9.14
12. SRNS
1
7.03
6.08
5.3
5.98
13. SRNS
1
8.73
8.66
9.96
9.54
14. SRNS
1
3.85
4.13
4.35
4.45
15. SRNS
1
18.9
15.45
8.64
12.29
16. SRNS
1
4.31
9.21
7.93
8.76
SDNS = steroid-dependent nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome.
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
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Zachwieja et al: Efficacy and safety of rituximab
Discussion
Referring to the research of recent years, which suggests
the possibility of safe and effective use of rituximab treatment as an alternative therapy in children with primary
and secondary chronic glomerulonephritis, we attempted
to summarize our own experience in this matter. Rituximab, a chimeric monoclonal antibody against the lymphocyte B CD20 protein, was brought into use in 1986 for
the first time (12). The exact mode of action of rituximab
is presumably connected with the Ca²+ ion influx across
plasma membranes, complement-mediated cell lysis with
direct or antibody-mediated apoptosis, and as a final result lymphocyte B down-regulation. Depletion of malignant B cells caused by rituximab is reflected in treatment
of hematological neoplastic diseases (13). Currently due
to its antiinflammatory effect, it is also widely used in such
disorders as rheumatoid arthritis, autoimmune hemolytic
anemia, multiple sclerosis and systemic lupus erythematosus (14). Rituximab is also increasingly used in nephrology in kidney transplant recipients and as an alternative
immunosuppressive therapy in patients with glomerulonephritis not responding to standard treatment. The growing
interest shown by nephrologists in rituximab’s therapeutic
opportunities is associated with the hypothesis concerning B lymphocytes’ crucial role in the pathogenesis of the
nephrotic syndrome (15, 16). In our studies the dose of
rituximab established as 375 mg/m2 was administered by
intravenous infusion once weekly for 1 to 4 weeks, depending on the CD19 lymphocyte concentration. Smith
et al reported a single dose of rituximab as effective for
patients with SDNS. Regarding SDNS patients a similar
observation was made by Westphal et al (17, 18). Refer-
TABLE III
CD19 LYMPHOCYTE CONCENTRATIONS IN THE VARIOUS STAGES OF TREATMENT
Patient no.,
indication for
treatment
Number of
rituximab
pulses
Output CD19
lymphocytes (%)
at start of treatment
CD19 lymphocytes CD19 lymphocytes CD19 lymphocytes
(%) 1 month after
(%) 3 months after (%) 6 months after
rituximab infusion rituximab infusion rituximab infusion
1. SRNS
4
24
0
0
0
2. SRNS
4
6
0
0
1
3. SDNS
4
17
0.1
0
5
4. SRNS
1
27
0
0
17
5. SRNS
1
5
0
0
1.6
6. SDNS
1
15
0
0
2
7. SRNS
1
1
1
0
15
8. SRNS
4
7
0
0
2
9. SRNS
1
14
0
0
0
10. SRNS
1
16
0
8
19
11. SRNS
1
2
0
0
0
12. SRNS
1
9
0
0
8
13. SRNS
1
18
0
0
15
14. SRNS
1
10
0
0.1
0
15. SRNS
1
10
0
0
1.7
16. SRNS
1
11
0
0
0
SDNS = steroid-dependent nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome.
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ring to the concept of 4 rituximab doses proposed by
Bagga et al, in our study group, including in SRNS patients, remission was received after a single intravenous
drug infusion (19). In the group of 16 patients, 14 steroidresistant and 2 steroid-dependent, complete clinical and
biochemical remission 1 month after drug administration
was observed in 11 of them. Nakayama et al reported that
a single rituximab dose was associated with a delayed
therapeutic response, but this was not confirmed in our
study (20). There was no correlation between number of
doses and time of remission. After 6 months of observation 1 steroid-dependent and 6 steroid-resistant patients
responded to the therapy. Seven steroid-resistant patients
with DMP did not achieve complete remission, which was
different from the report of Bagga et al, who reported that
rituximab was efficacious in inducing remission in patients
with SRNS resistant to standard treatment with corticosteroids and calcineurin inhibitors (19). In our study group,
all of the patients who at baseline had negative proteinuria
remained in remission in the first 6 months of treatment.
In the remaining 10 patients with initial non-nephrotic proteinuria, only 3 maintained long-lasting remission. In all
patients responding to the treatment, its therapeutic result
was visible within the first month after a single intravenous
infusion. There were no statistically significant differences
in response to the treatment depending on the kidney biopsy result. In 3 of the 7 patients who did not achieve remission, diffuse mesangial proliferation was found.
Across all types of MPGN, the efficacy of various forms of
treatment including rituximab therapy remains controversial. Some authors recommend long-term steroids as effective in children with nephrotic-range proteinuria (21). However, it should be noted that in a group of 6 DMP patients,
exactly half of them achieved remission. This justifies an
attempt of rituximab treatment in any patient with primary
or secondary glomerulonephritis and an unsatisfactory
result with standard therapy. The efficacy of rituximab is
insufficient especially in some steroid-resistant patients.
This phenomenon might be explained by the presence of
antibodies against the human-mouse chimeric protein or
gene polymorphism for receptor required for RTX binding
to phagocytes (22, 23). In our study group, the decisive
factor for the success of treatment was the initial occurrence of proteinuria at the time of its inception. The presence of proteinuria at baseline was a negative prognostic
factor. We did not observe differences in terms of either efficacy or occurrence of any adverse effects between single
and multiple starting rituximab doses. After 6 months, consistent with the pharmacokinetics of rituximab, restoration
of CD20 cell number, regardless of sustained remission,
had a decisive influence on the decision of a single repeat dose. We did not observe changes in average total
leukocyte count, which was stable throughout the time
of observation. These facts in our opinion support single
intravenous rituximab pulse administration at a dose of
375 mg/m2 every 6 months. We are aware of the need to
continue current therapy in the study group, but are currently unable to determine the probable time of its duration and safety. We are considering the possibility of adding
mycophenolate mofetil to maintain the remission without
a rituximab repeat dose, according to the suggestion of
Filler et al (24). Nearly all treated children receiving the
drug experienced flu-like symptoms. Predominant side
effects were abdominal pain, headache, increased body
temperature, fever and nausea lasting up to several hours.
We did not observe any major potential complications of
rituximab therapy (25, 26).
Conclusions
In conclusion, we postulate that alternative rituximab therapy should be taken into consideration in nephrotic patients
not responding to standard therapy. In this group, the potential benefits of the therapy may outweigh the expected
side effects.
Financial support: No grants and funds were received to perform
this study.
Conflict of interest statement: None of authors has conflict of
interest.
Address for correspondence:
Prof. Jacek Zachwieja, MD, PhD
Department of Pediatric Nephrology
Poznan University of Medical Sciences
Szpitalna 27/33 Street
PL-60-572 Poznan, Poland
[email protected]
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
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Zachwieja et al: Efficacy and safety of rituximab
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Accepted: December 09, 2011
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428