Abstract
Minimal change disease (MCD) is one of the most common pathological
types of primary nephrotic syndrome. High-dose glucocorticoid therapy is
the initial treatment for MCD; however, the long-term use of high-dose
glucocorticoids can lead to serious adverse events. Therefore, research
into non-hormone-containing regimens is increasing. In recent years,
There has been some progress in the use of rituximab for the treatment
of refractory, steroid-dependent, or relapsing MCD. However, little
research has been conducted on the use of rituximab as the initial
treatment option for MCD. This paper reports the results of treating
five patients with confirmed MCD using a single-agent anti-CD20 antibody
regimen. Our results show that anti-CD20 antibody is effective as a
first-line treatment for adult MCD without significant adverse
reactions. In addition, we reviewed the currently published literature
and found there are two series of case reports of RTX as first-line
treatment for MCD in adults. The results of these two series of cases
also show that anti-CD20 antibody is effective as a first-line treatment
for adult MCD without significant adverse reactions. This regimen
provides more options for patients who are unwilling to use hormones or
have contraindications for hormone use.
Introduction
Minimal change disease (MCD) is the third most common primary kidney
disease (10% to 17%) in adults with idiopathic nephrotic syndrome
(NS)1. Steroids have been widely used to treat
adult-onset MCD since the early 1970s. However, 10% to 30% of adults
with MCD fail to respond to corticosteroids2, 70% to
80% relapse after NS remission2, 10% to-30% occur
frequently relapse, and 15% to 30% become steroid
dependent3. Additionally, adverse effects of long-term
corticosteroid use remain a significant challenge in clinical practice.
Few studies have shown that these alternative regimens, such as
cyclophosphamide (CyC), cyclosporine (Cys)4,
tacrolimus (TAC)5, and low-dose prednisone with
mycophenolate (MPA)6, as first-line treatments for
MCD, have no obvious advantages in terms of either efficiency or adverse
effects compared with corticosteroids. Therefore, newer treatments for
adult MCD should be explored to improve the remission rate and reduce
the risk of side effects.
Cell depletion agents include chimeric, human, and humanized
monoclonal anti-CD 20 antibodies. Rituximab (RTX) is a chimeric
anti-CD20 monoclonal antibody first applied to MCD in
20067. Since then, it has been used to treat
relapsing NS in children]. A recent study showed that RTX could be
used to treat frequently relapsing and glucocorticoid-dependent MCD in
adults, leading to a reduction in the frequency of relapse and
facilitation of glucocorticoids withdrawal8, 9. New
human and humanized monoclonal anti-CD20 antibodies offer some
advantages based on their stronger effects on CD20 cell subtypes, and
have already been administered in hematology and oncology as
substitutes for chimeric molecules; however, research on their
application in glomerular diseases is limited. Whether anti-CD20
antibody is the best front-induction therapy for MCD remains to be
explored. In this article, we retrospectively reviewed the efficacy
and safety profile of the anti-CD20 antibody as an initial treatment
for five biopsy-proven adult patients with MCD. Furthermore, we
analyzed the previous literature on RTX applied to the front MCD to
deepen our understanding of this issue.
Case series report
Five adult patients with renal biopsy-proven MCD were enrolled in the
study. The patients were initially treated with anti-CD20 antibodies
because of their unwillingness to use glucocorticoids or
glucocorticoid-related side effects. All patients received at least one
course of anti-CD20 (rituximab, RTX, or obinutuzumab, OTZ ) antibody
treatment (two infusions of 1000 mg every 14 days). Therapeutic effects
were assessed by measuring 24-hours urinary protein and serum albumin
levels. Complete remission (CR) was defined as 24-hours urinary protein
defined as a decrease in 24-hours urinary protein of more than 50% from
the baseline.
Case 1
A 74-year-old woman was diagnosed with an MCD in July 2022. She had
hypertension for more than 20 years and impaired glucose tolerance (IGT)
for one year. The Body Mass Index (BMI) was 24.6 kg/m2. Laboratory
analyses revealed a urinary protein level of 4745 mg/day, serum albumin
(ALB) level of 26 g/L, serum total cholesterol (TC) level of
8.44 mmol/L, and serum IgG 6.12g/L(Table 1). The patient was initially
treated with RTX on August 4th and August 18th 2022. The patient was
followed-up for 18 months. She achieved partial remission (PR) with a
decreased urinary protein level from 5724 mg/d to 2134 mg/d 1 month
after treatment and achieved complete remission (CR) within 3 months.
CD19+ cells were monitored during follow-up. Six months after receiving
RTX, although CD19+ cells were undetectable, the disease relapsed with
increased urinary protein levels from 267 mg/day to 4587 mg/day. She
then received RTX (1 g) again and achieved a >50% decrease
in urinary protein excretion three months after the second infusion of
RTX. At the last follow-up, the urinary protein level was less than 1
g/day, and ALB, serum IgG, and TC levels were normal. The renal function
remained stable during the follow-up period (Table 2).
Case 2
A 71-year-old man was diagnosed with MCD in September, 2022. He had
urarthritis for more than 10 years. BMI was 22.4 kg/m2. Subsequent
laboratory tests showed a urinary protein level of 6541 mg/day, ALB
level of 21 g/l, and TC level of 8 mmol/L (Table 1). RTX treatment on
September 22 and October 7, 2022. Proteinuria declined in months 1 and 3
to 1678 mg/day (PR) and 178 mg/day (CR), respectively. Peripheral CD19+
cells were undetectable until nine months after RTX treatment. At the 24
months follow, the patient’s renal function was stable and CR was
maintained (Table 2).
Case 3
An 18-year-old man was diagnosed with MCD in September 2022. The patient
had no relevant medical histories. BMI was 21.4 kg/m2. Results from a
24-hours urine protein excretion test detected 23445 mg of protein. TC
and ALB were 17.76 mmol/L and 12 g/L, respectively (Table 1). He
received OTZ on September 9 and 24, 2022. One month after the start of
OTZ treatment, the patient responded with a Stable as 24 hours protein
decreased of 96.5% (from 23445 to 832 mg/day). The urinary protein
levels were normal by the third month (Table 1). It is worth noting that
peripheral CD19+ cells remained depleted by 18 months follow-up (Table
2).
Case 4
A 29-year-old woman was diagnosed with an MCD in September 2021. The
patient had no relevant medical histories. BMI was 25.9 kg/m2.
Laboratory tests revealed massive proteinuria (15, 651 mg/day),
decreased albumin (17 g/L), and elevated cholesterol (7.47 mmol/L), as
shown in Table 1. RTX infusion was administered on September 8, 2021,
and September 26, 2021. Her urine protein level decreased to 394 mg/day
two weeks after the first dose of RTX, and she still received a second
dose of RTX according to the initial regimen. Peripheral CD19+ cells
recovered nine months after RTX treatment (Table 2). No relapse has been
documented for more than three years of follow-up. Fortunately, she has
successfully given birth to a healthy child, and the disease remains in
remission.
Case 5
A 58-year-old man diagnosed with MCD in August 2021. He had a history of
hypertension for more than five years, IGT for one month, and
urarthritis for three years. BMI was 26.3kg/m2. Major biological
abnormalities were observed in laboratory tests: low ALB (24 g/L),
massive proteinuria (7924 mg/L), and elevated cholesterol (8.38 mmol/L).
Immuno-electrophoresis revealed IgM κ,IgM with 2.59 g/L (reference
range: 0.46-3.04), IgG with 4.28 g/L (reference range: 7.51-15.6), and
IgA with 3.38 g/L (reference range: 0.82–4.53) (Table 1). Bone marrow
aspirate, immunophenotypic analysis of bone marrow cells, and
kappa/lambda-free light chains (FLCs) showed normal results, and
multiple myeloma diagnoses were discarded. The patient was treated with
RTX on August 11th and 27, 2021. Proteinuria decreased at a slower rate
in this patient than in the previous four patients. The time to achieve
PR and CR was 3 and 12 months, respectively (Table 2). Peripheral CD19+
cells were detected six months after RTX infusion. RTX offers sustained
and long-term remission (> three years).
Overall, only Patient 1 received repeated RTX therapy and eventually
achieved PR. The other four patients received only one course of RTX or
OTZ treatment, maintained a sustained CR, and were relapse free. All
five patients were administered antiallergic symptomatic treatments
before RTX or OTZ infusion to avoid infusion-related symptoms. There
were no infusion-related hematological reactions or any other serious
adverse events at the end of follow-up.
Literature reviews
Research on the use of anti-CD20 antibodies as first-line treatment for
MCD is limited. We found two series of case reports of RTX as first-line
treatment for MCD in adults. In one case series report, eight patients
were treated with a single dose of RTX (375 mg/ m2) and one patient with
RTX (1 g twice). Five of the nine patients achieved CR, one patient
achieved PR, two patients had no remission, and one patient
relapsesed10 (Table 3). Another case series included
six patients treated with RTX (four weekly doses of 375 mg/m2); five
patients achieved CR, and one achieved PR11 (Table 3).
No serious adverse events were reported in either of the studies.
Based on these reports and our clinical experience, RTX is useful for
inducing and maintaining remission in adult patients with initial MCD.
The initial dose of RTX was different in the published reports. In the
Guan N series, all the patients received small doses of RTX. In Fenoglio
R’s series and our series, all patients received a higher dose regimen,
and the results showed that all but one patient experienced sustained
remission over a prolonged follow-up and did not require repeated
infusions. It is worth discussing whether a higher initial dose regimen
can lead to protracted remission.
Discussion
However, the underlying pathogenesis of MCD is not yet fully understood.
Although MCD has long been recognized as a T cell-mediated disease, the
role of B cells in MCD has gained attention owing to the successful use
of B cell-depleting agents. Recently, MCDs were reported to have several
functions. 1) Production of pathogenic antibodies: The Ubiquitin
Carboxyl-Terminal Hydrolase L1 (UCHL1) antibody causes podocyte
detachment in vitro and is associated with the relapse of idiopathic NS
in mice12. Nephrin autoantibodies, which are present
in almost 1/3 of patients with MCD, may cause loss of slit diaphragm
architecture and are associated with disease
activity13. 2) B cells are involved in the
pathogenesis of MCD, possibly by producing cytokines such as IL-4. In a
murine model, local activation of B cells induced foot effacement and
proteinuria through the production of IL-414. 3)
B-cell depletion may lead to a new balance between T cell subsets. One
study showed that RTX-treated patients had a low frequency of variant
natural killer T (iNKT) and might induce qualitative alterations in CD4+
follicular T cells (TFH cells), thus inhibiting the reconstitution of
switched memory B cells, which has been associated with
steroid-dependent MCD disease activity 15, 16. With
more attention paid to the role of B cells in MCD, B cell depletion
agents are widely used in the treatment of frequently
relapsing/steroid-dependent MCD8, 17, and have
achieved good clinical results. However, it is unknown how these drugs
function during the first MCD episode.
Based on limited case reports, RTX has shown efficacy and an acceptable
safety profile as a first-line induction regimen in adults with MCD. In
our series, one patient was treated with obinutuzumab (OTZ) (two doses
of 1,000 mg), a type II humanized anti-CD20 monoclonal antibody.
According to previous reports, fully human and humanized anti-CD20
antibodies demonstrate stronger in vitro activities than RTX, and OTZ
may offer some advantages over RTX18. In a recent case
series, OTZ was effective in membranous nephropathy that failed to
respond to RTX19. In MRL/lpr mice, a murine model of
Lupus, OTZ was more effective in depleting B cells than
RTX20. A Randomized Controlled Study showed that OTZ
provided a longer sustained clinical benefit than RTX in Proliferative
Lupus Nephritis20. The patient achieved PR in the
first month, CR in the third month, and sustained remission for one
year. Notably, his peripheral CD19+ cells remained depleted for longer
than those in the other four patients. One study showed that the
proportion of CD19 recovery in patients with relapse is
higher8, 21. However, another study showed that
ofatumumab (a fully human anti-CD20 monoclonal antibody) was not
superior to RTX in maintaining MCD remission in children and young
adults, although ofatumumab treatment resulted in more prolonged
depletion of B cells22. Whether fully human and
humanized anti-CD20 antibodies are superior to RTX for the initial
treatment of MCD requires further investigation.
The optimal initial dose of anti-CD20 antibodies for adults with MCD
remains unknown. At present, there are no reports on the application of
OTZ in MCD. Different dosing protocols of RTX include 1) one, two,
three, or four weekly rituximab infusions of 375 mg/m223-27. 2) 500 mg 2 weeks apart28. 3)
One gram, once or on days 1 and 1525 is frequently
used for relapsing/steroid-dependent MCD. However, these studies showed
no correlation between the different treatment regimens or conclusions
could not be drawn owing to the small size of the treatment subgroups.
Studies on RTX administered alone as front induction therapy in adult
MCD are rare. Therefore, it is difficult to determine the optimal
initial dose based on the current results because of the limited number
of patients treated. Hence, controlled trials are urgently needed to
compare the different dosing protocols for MCD.
Another key issue is that the optimal dosing timing for RTX
re-administration to maintain remission remains unclear. Studies have
shown that the risk of relapse is associated with B-cell reconstitution
after RTX8, 21. Other studies have shown that
remission may persist despite complete B-cell recovery, and relapse can
occur in the presence of sustained depletion of B
cells21, 29, 30. In our study, Patient 1 relapsed six
months after RTX infusion, while CD19+B cells were still undetectable.
The remaining four patients reached CR and were relapse-free, even with
CD19+ B-cell recovery. Hence, it is not accurate to determine the timing
of administration based on whether the B cells are reconstructed.
However, further studies are required to confirm these results.
Adverse reactions to anti-CD20 antibodies should be considered. Among
the patients included in this study, no serious side effects that might
have been caused by RTX or OTZ were observed. The most common concerns
revolve around infusion reactions such as hypotension and allergies.
These issues could be addressed by using supportive drugs and adopting
slow infusion. Regarding long-term adverse reactions to RTX, one study
showed that RTX as induction and maintenance therapy in ANCA-associated
vasculitis was followed for an average of 2.1 years, and no significant
adverse reactions were observed31. In another study on
lupus nephritis, OTZ did not carry a higher risk of serious adverse
events or infections at 52 weeks of follow-up32. All
patients were administered anti-CD20 antibodies alone, and the longest
follow-up period was 37 months with no recurrence or adverse reactions.
Therefore, RTX and OTZ showed favorable long-term safety profiles.
This study has some limitations. The number of patients was small
because anti-CD20 antibodies as a first-line treatment for MCD are
limited owing to the higher out-of-pocket costs. Moreover, there was no
control group in this study, and there remains needs for further studies
whether anti-CD20 antibody as first-line treatment for MCD are superior
to steroids in terms of therapeutic efficacy and adverse effects in
first-line treatment of MCD. All patients in this study achieved CR
regardless of whether they were treated with OTZ or RTX, and only one
patient relapsed. Whether humanized anti-CD20 has any advantage over
chimeric mAbs in the treatment of MCD remains unclear.
Conclusion
In conclusion, the extremely positive results obtained with anti-CD20
monoclonal antibody in the first episode of MCD suggest the possibility
of considering this regimen as first-line treatment, providing more
options for patients with steroid contraindications. Several key
questions remain to be addressed in future clinical trials, including
whether anti-CD20 antibody is superior to steroids, the optimal dosing
and timing for repeated infusion to maintain CR, and whether humanized
anti-CD20 should be preferred over chimeric monoclonal antibodies.