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Indian Pediatr 2017;54:
49-50 |
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Repeated Administrations
of Rituximab along with Steroids and Immunosuppressive Agents in
Refractory Steroid-resistant Nephrotic Syndrome
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Shuichiro Fujinaga and *Koji Sakuraya
From Division of Nephrology, Saitama Children’s
Medical Center and *Department of Pediatrics, Juntendo University School
of Medicine; Japan.
Correspondence to: Dr Shuichiro Fujinaga, Division of
Nephrology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ku,
Saitama-city Saitama 339 8551, Japan.
Email: [email protected]
Received : August 26, 2015;
Initial review: December 19, 2015;
Accepted: October 04, 2016.
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Background: A recent randomized control trial in
children with steroid-resistant nephrotic syndrome revealed that two
doses of rituximab did not reduce proteinuria. Case characteristics:
A 14-month-old boy developed refractory steroid-resistant nephrotic
syndrome due to focal segmental glomerulosclerosis. Observation:
The patient achieved complete remission 11 months after disease onset
following eight doses of rituximab combined with steroids and
cyclosporine. Message: Long-lasting B cell depletion with
repeated rituximab administrations may be required to achieve complete
remission in patients with steroid-resistant nephrotic syndrome and
massive proteinuria.
Keywords: Cyclosporine, Focal segmental glomerulosclerosis,
Treatment failure.
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T he chimeric monoclonal
anti-CD20 antibody rituximab (RTX) has recently emerged as a therapeutic
option for refractory steroid-resistant nephrotic syndrome (SRNS).
Bagga, et al. [1] reported the efficacy of treatment with four
doses of RTX in five patients with nephrotic syndrome resistant to
treatment with high-dose corticosteroids, alkylating agents, and
calcineurin inhibitors [1]. In another study, a single dose of RTX was
not effective in inducing remission in children with SRNS [2].
Furthermore, a recent randomized control trial in 31 children with SRNS
revealed that two doses of RTX did not reduce proteinuria at three
months [3]. We report the case of a child with refractory SRNS due to
focal segmental glomerculosclerosis (FSGS) who achieved complete
remission 11 months after disease onset, following repeated
administration of RTX.
Case Report
A previously healthy 14-month-old boy diagnosed with
idiopathic nephrotic syndrome was initially admitted to another hospital
with generalized swelling and significant weight gain. Perinatal history
was normal and family history was negative for renal disease. Despite
treatment with high-dose prednisolone (2 mg/kg/day), he developed acute
kidney injury and was referred to our center. Physical examination
revealed generalized edema, abdominal distention, and a blood pressure
of 106/63 mmHg. Laboratory findings were as follows: blood urea nitrogen
46 mg/dL, serum creatinine 0.34 mg/dL, sodium 125 mmol/l; potassium 4.1
mmol/l, calcium 7.9 mg/dL, phosphorous 4.7 mg/dL, total protein 3.6 g/dL,
albumin 1.8 g/dL, total cholesterol 526 mg/dL, and serum IgG 93 mg/dL.
Urinalysis by dipstick revealed 3+ occult blood and 4+ protein. Urinary
protein/creatinine ratio (U-P/C) was 156.9 and the 24-h urinary protein
excretion was 21 g (2 g/m 2/h).
After two weeks of hemodialysis, the patient’s renal function improved.
However, persistent heavy proteinuria for >4 weeks with high-dose PSL
led to a diagnosis of SRNS; renal biopsy showed features of FSGS and
electron microscopy showed diffuse foot process effacement (>80%).
Genetic mutation for NPHS2 and WT1 was negative. We
treated the patient with intravenous methyl-prednisolone (20 mg/kg/day
for 3 consecutive days per week) for 3 weeks, followed by cyclosporine (CsA;
6-7 mg/kg/day) and alternate-day prednisolone (1.5 mg/kg). However, the
patient developed AKI again, which prompted the decision to switch from
CsA to mycophenolate mofetil, and to initiate peritoneal dialysis. After
4 weeks of peritoneal dialysis, the renal function recovered and the
patient was re-treated with CsA. However, massive proteinuria (11-18
g/day, U-P/C 120-200 g/g) persisted, and the patient required albumin
infusions for more than two months. Therefore, we treated the patient
with a combination of 2-weekly doses of RTX (375 mg/m2)
and additional intravenous dose of methylprednisolone. However, there
was no significant reduction in proteinuria, and complete B cell
depletion (CD19 cell 0%) was not achieved, despite administration of the
two doses of RTX. The serum RTX levels just after the first and second
dose were 232.1 and 223.6 µg/mL, respectively; thereafter, the levels
fell very quickly and were 5.1 and 2.6 µg/mL at 7 days after the first
and second dose, respectively. We administered two additional doses of
RTX followed by intravenous methyl-prednisolone and a second course of
high-dose prednisolone (2 mg/kg/day), leading to complete B cell
depletion and a subsequent marked decrease in proteinuria (<1 g/day,
U-P/C 1-10 g/g). This treatment strategy resulted in the discontinuation
of albumin infusions without the development of edema. At 54 days after
the complete B cell depletion with fourth RTX infusion, re-emergence of
CD19 cells (0.7% of total lymphocyte count) was detected and 4 more RTX
infusions were added (total 8 doses), which maintained a long-term B
cell depletion for the next four months. The serum RTX levels just after
the fifth dose was 274.4 µg/mL. In contrast to the rapid decrease in the
serum RTX levels following the first and second dose, at 10 days after
the fifth dose, the patient had sustained the serum RTX levels at 75.4
µg/mL. At two months after the last (eighth) RTX infusion (11 months
after the disease onset), he finally achieved complete remission and
prednisolone was gradually tapered off. At the age of 3 years and 5
months, he maintained in complete remission with cyclosporine
monotherapy despite the re-emergence of CD19 cells.
Discussion
Despite the increasing use of RTX in children with
refractory nephrotic syndrome, very little information is available on
its pharmacokinetics, particularly in SRNS. In this case, we observed
that the serum RTX levels declined more rapidly during a phase of
massive proteinuria, indicating the need of its repeated administration
at shorter intervals in patients with refractory SRNS. We previously
reported that the mean serum half-life of RTX in patients with
steroid-dependent nephrotic syndrome (SDNS) during a proteinuria-free
period was 14.6 days [5], and the mean duration from the RTX
administration until B cell was detectable was 5.1 months [6].
Counsilman, et al. [7] reported a very short (<1 day) serum
half-life of RTX in a 10-year-old patient with SRNS, during a phase of
nephrotic-range proteinuria [7]. Considering the potential losses
through urine, more frequent dosing of RTX may be required to maintain
the serum RTX levels, particularly in patients with SRNS.
Although RTX is regarded as a relatively safe
treatment for children with idiopathic nephrotic syndrome, various
adverse events such as late-onset neutropenia, hypogammaglobulinemia,
and increased risk of infections, have been rarely reported [8].
Although our patient did not have neutropenia and bacterial infections
after RTX therapy, despite a lack of significant proteinuria, severe
hypogammaglobulinemia (184 mg/dL) requiring intravenous gammaglobulin
developed at two months after the last (eighth) RTX infusion.
We conclude that long-lasting B cell depletion with
repeated RTX administrations at shorter intervals may be required to
achieve complete remission in children with SRNS and severe proteinuria.
Studies are needed to determine the optimal doses of RTX and suitable
concomitant immunosuppressive agents for refractory SRNS.
Acknowledgement: Chugai Pharmaceutical Co, Ltd.
(Tokyo) for the measurement of serum rituximab concentrations.
Contributors: Both authors have
contributed to patient management and manuscript writing.
Funding: None; Competing
interests: None stated.
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