Transcript New therapy for Glomerular Diseases 'Practical or

NEW THERAPIES FOR GLOMERULAR DISEASES
"PRACTICAL OR THEORETICAL – FACT OR
FICTION"
Mohamed sobh MD,FACP
Professor of Nephrology , Urology &
Nephrology
Center
Director of Medical Experimental Center
MERC
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Immunologically mediated glomerulonephritis occurs
as a primary disorder or in association with a
multisystem disease,such as SLE or vasculitis, and is a
potentially preventable cause of ESRD.
With the exception of renin and angiotensin blockade,
current therapy relies on nontargeted glucocorticoids
and cytotoxic or antiproliferative drugs and has
changed little during the careers of currently
practicing nephrologists.
With the success of biologic agents, Rituximab in
particular, in autoimmune arthritis, multiple sclerosis,
and transplantation, attention is turning to
autoimmune renal disease.
BIOLOGIC AGENTS - TARGETED DRUGS
Rituximab
 ACTH
 Abatacept
 Eculizumab
 Oral Galactose
 Enteric Budesonide
 Others
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RITUXIMAB
Rituximab is a murine/human chimeric anti-CD20
mAb that depletes B cells and was licensed in 1997 for
the treatment of non-Hodgkin’s lymphoma.
 A subsequent expansion of interest in Rituximab as an
immunomodulatory agent resulted in a label for
rheumatoid arthritis in 2006 and preliminary reports
of efficacy across the spectrum of autoimmune disease.
 More than 20 studies of almost 300 patients reported
response rates averaging 75% in refractory lupus or
lupus nephritis treated with rituximab.
 Responses are accompanied by falls in anti– doublestranded DNA antibodies, correction of complement
depletion, and reduction in glucocorticoid requirement.
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A near universal finding has been the achievement of
peripheral B cell (CD19 or CD20 lymphocytes)
depletion below 1 106/L after rituximab, and failure to
achieve depletion is correlated with poor or no clinical
response.
B cell recovery is detectable after 6 to 9 mo, and
although prolonged B cell depletion is associated with
a prolonged clinical response, B cell return is not
closely associated with disease activity, and relapses
have occurred before B cells return.
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Polymorphisms in the FcRIII receptor influence
rituximab-induced B cell lysis and associate with
incomplete B cell depletion with low-dosage
rituximab .
The development of antichimeric antibodies to
rituximab is found in up to 30% of treated
patients; although in the majority of cases they
seem to have no clinical effect .
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The preliminary results in lupus and vasculitis
have stimulated the design of randomized,
controlled trials with a humanized anti-CD20
mAb, ocrelizumab, and a B cell– depleting anti
CD22 mAb, epratuzumab. B cell– modulating
drugs, including anti-BLyS, belimumab, and the
soluble TACI receptor atacicept, which blocks
BLyS and APRIL signaling, are also being
studied
in systemic lupus.
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Rituximab is now considered an alternative therapy
for refractory lupus, lupus nephritis, and vasculitis,
but there is no current evidence supporting its use in
routine care for remission induction or maintenance,
and there is less evidence in primary
glomerulonephritis.
B cell– depleting or –modulating drugs have the
exciting potential of improving control of
glomerulonephritis and avoiding or minimizing
exposure to glucocorticoids and immunosuppressive
drugs.
RETUXIMAB AND MN
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Most of the reported experiences with rituximab are from
uncontrolled pilot trials or case series from two centers in
Bergamo, Italy, and the Mayo Clinic in the United States.
The following treatment protocols have been tried for IMN : four
weekly doses of 375 mg/m2, which is standard dosing for
treatment of lymphoma; two 1000-mg doses given biweekly,
which is standard for rheumatoid arthritis; and a B cell–driven
protocol in which dosing is titrated to the number of circulating B
cells.
Among nephrotic patients with IMN, the four-dose lymphoma and
two-dose arthritis regimens seem to have similar efficacy despite
faster B cell recovery after the two-dose regimen. no detectable
differences in the progressive reduction of anti-PLA2R levels
between the two dosing regimens
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A recent study by Ruggenenti et al. [2012] looked
at 100 patients treated with rituximab for
idiopathic MN. 27% of the patients had a
complete and 38% a partial remission of the
nephrotic syndrome.
The authors feel this may be a first line agent for
some patients.
However, this was not a randomized controlled
trial.
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Regardless of the regimen administered, proteinuria
tends to decline slowly and remissions may occur up to 2
years after treatment.
Interestingly, Beck et al. 2011, showed that after
administration of rituximab, the median time to reach
undetectable anti-PLA2R levels was 9 months (range, 1–
18 months).
This may explain the delay in remissions, because the
reduction in antibody levels seems to precede the decline
in proteinuria by months.
It is interesting to note that remissions continue to occur
well after the end of therapy with rituximab or
alkylating agents; complete remissions can be seen 12
months after the completion of these interventions. This
is in contrast to what is observed after cyclosporine or
tacrolimus, in which typically no additional remissions
occur once treatment stops.
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Relapse rates after rituximab therapy are
difficult to estimate given the limited
longitudinal data.
There are two published studies (n=31) that
followed patients for up to 24 months and
relapses were infrequent (6% and 13%,
respectively).
Currently, there are no established guidelines
regarding the issue of retreatment and
investigators have taken different approaches.
Empirical redosing, B-level, protienuria, PLA2R .
RITUXIMAB AND FSGS
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Rituximab has been used in small trials of nephrotic patients
with FSGS.
In several of these studies, some patients with steroid-resistant
nephrotic syndrome or biopsy- documented FSGS have responded
to this therapy.
In corticosteroid-dependent or relapsing nephrotics the drug has
led to reduction of proteinuria and the ability to decrease other
immunosuppressive agents.
Recently, however, results have been disappointing in
corticosteroid- resistant patients ,Magnasco A et al 2012.
In this trial they found no benefit in the addition of rituximab in
terms of remissions or reducing other immunosuppressives.
A Spanish collaborative group found that of 8 patients with
steroid-resistant FSGS, only 3 responded and even they needed a
repeat course of the drug.
Thus, this agent has been somewhat disappointing so far in
treating resistant FSGS.
TOXICITY
Although acute infusion reactions are often mild and
manageable (e.g., fever, chills, pruritus, and skin
rash), more severe and potentially fatal reactions (e.g.,
acute respiratory distress syndrome, bronchospasm,
angioedema, shock and myocardial infarction) as well
as potentially fatal mucocutaneous reactions (e.g.,
Stevens–Johnson syndrome and toxic epidermal
necrolysis) can occur.
 Rare cases of the devastating demyelinating central
nervous system disease, progressive multifocal
leukoencephalopathy, have also been reported,
although typically when administered as part of
multidrug immunosuppressive regimens.
 Finally, the long-term safety profile of rituximab in
glomerular diseases is largely unknown, particularly if
repeated courses are needed.
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Controlled prospective trials are needed to
compare the efficacy and toxicity of rituximab
with CNIs and cytotoxic drugs.
More data are needed to clarify the role of
rituximab in patients with impaired or
declining renal function and the effects of
rituximab on hard endpoints such as dialysis
and death.
ACTH
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Although listed as a new therapy for glomerular diseases, the natural
pituitary hormone ACTH has been FDA-approved for treatment of the
nephrotic syndrome since the 1950s.
Its resurgence has come as a result of the successful use in Europe of
synthetic ACTH, in treating the nephrotic syndrome,Berg Al.2004.
In some such studies, several patients with FSGS had dramatic
decreases in proteinuria after treatment with ACTH.
In subsequent publications some patients resistant to other therapies
have responded well to natural ACTH treatment Bomback AS et
al,2011,2012.
A small multicenter randomized control trial of 32 patients by Ponticelli
et al.2006 compared efficacy of 6 months of alkylating agents
alternating with corticosteroids to tetracosactrin intramuscular
injections for 1 year (1 mg twice weekly).
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There were no significant differences in cumulative remission rates
between the treatment arms ,initially (93% versus 87%, respectively) or
at final follow-up of 21 months (75% total versus 87%, respectively).
However, it is notable that these patients were treatment naïve, with
preserved kidney function and low to modest degrees of proteinuria (5–6
g/d)—all of which may lead to an overly optimistic view of remission
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Outcomes were not as favorable in a recent
prospective study from the Netherlands in which
tetracosactrin was administered to high-risk
IMN patients ( Hofstra j,et al 2011).
After 9 months of treatment, only 44% of patients
achieved remission and relapse rates were high
(43%).
Other investigators have reported similarly high
relapse rates after drug discontinuation,
particularly after short courses of therapy.
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A different formulation of ACTH, a natural
highly purified gel, is available in the United
States (corticotropin; Questcor Pharmaceuticals
Inc, Anaheim Hills, CA).
In a retrospective study of corticotropin in
proteinuric glomerular diseases, 9 of 11 (82%)
patients with IMN achieved a remission (three
complete; six partial).
Interpretations of the data are limited due to the
uncontrolled nature of the study, the variable
dosing regimens used, a possible carry-over effect
from previously administered
immunosuppression, and short follow-up
The mechanisms by which ACTH exerts its
antiproteinuric effect are not understood.
 The effects are not thought to be mediated by
induction of endogenous cortisol from the adrenal
glands because administration of corticosteroids as
monotherapy has not been effective in IMN.
 recently, attention has focused on a possible direct
effect of ACTH on podocytes as expression of one of the
natural receptors for endogenous ACTH (melanocortin
receptor-1) has been identified in human kidney
tissue, mainly in the podocyte ,lindskog A et al 2010.
 In support of this theory, experimental evidence in a
rat model of membranous disease showed that
treatment with an agonist of the melanocortin
receptor-1 reduced proteinuria and improved podocyte
morphology compared with untreated rats.
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ACTH AND FSGS
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Two recent studies looked specifically at
treatment with ACTH in resistant FSGS and
found promising results .Lafayette R,2012,
Hagan jj,2012.
In one from Stanford University, proteinuria
was significantly reduced in a group of 12 FSGS
patients
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In the other study, from Columbia University, 12
FSGS patients who had failed on average three
immunosuppressive regimens (e.g.
corticosteroids, CNI, mycophenolate, etc.) were
treated with Acthar gel 80 units twice weekly for
6 months.
Five of these patients had a solid response to
treatment with major sustained drops in
proteinuria and/or reduction of serum
creatinines.
Thus, ACTH may be a viable therapy for
resistant FSGS patients.
The experience with ACTH, particularly
in the United States, is far too
preliminary to consider using this
treatment outside of clinical research
studies.
ABATACEBT
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Abatacept (CTLA-4–Ig) is an inhibitor of the T-cell costimulatory
molecule B7-1 (CD80).
It is currently approved for the treatment of rheumatoid arthritis
and has been used to treat other autoimmune diseases.
B7-1 is induced in podocytes in various animal models of proteinuria.
Podocyte B7-1 expression is not evident in normal human kidney
podocytes but is found in patients with certain glomerular diseases.
The analysis of a series of 22 randomly selected biopsy specimens of
native human kidneys identified a subpopulation of patients with
minimal- change disease or primary FSGS who had B7-1
immunostaining of podocytes.
In contrast, immunostaining for B7-1 was negative in 4 of 5 biopsy
specimens obtained from patients with secondary FSGS, despite
substantial podocyte injury.YU etal,2013.
Yu etal, also observed B7-1 staining in every biopsy specimen from
patients with recurrent FSGS ,Chih-Chuan Yu etal,2013.
EDITORIALS
N ENGL J MED 369;25 NEJM.ORG DECEMBER 19, 2013 ,2453
A NEW ERA OF PODOCYTE-TARGETED THERAPY FOR PROTEINURIC
KIDNEY DISEASE
BÖRJE HARALDSSON, M.D., PH.D.
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Yu and coworkers 2013, now propose in the Journal a novel therapy for
proteinuric kidney disease that targets the podocytes.
The authors introduce a new classification for proteinuric kidney disease
by dividing it into B7-1 (CD-80)–positive or B7-1– negative, according to
whether there is immunostaining for this costimulatory molecule.
Patients with B7-1 staining in their renal-biopsy specimens have
podocytes that express the B7-1 protein, which normally is absent.
The authors found that B7-1–positive podocytes have a reduced capacity
to attach to the surrounding matrix through β1 integrin.
They report that B7-1–positive podocytes change their morphologic
characteristics and their function, leading to detachment of podocyte foot
processes from the glomerular basement membrane and giving rise to
proteinuria.
Furthermore, the authors found that administration of abatacept, an
inhibitor of B7-1, appears to cure patients with severe nephrotic
syndrome due to primary focal segmental glomerulosclerosis (FSGS) or
recurrent FSGS after transplantation.
This article was published on November 8,
2013, at NEJM.org.
N Engl J Med 2013;369:2416-23.
DOI: 10.1056/NEJMoa1304572
Structural features of Eculizumab
ECULIZUMAB
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eculizumab, a humanized monoclonal antibody
that binds with high affinity to C5 thereby
blocking the terminal complement complex and
preventing the generation of the membrane
attack complex (MAC).
Eculizumab has been approved for the treatment
of paroxysmal nocturnal hemoglobinuria (PNH)
and atypical hemolytic uremic syndrome (aHUS).
It has also been used in a small number of
patients with C3GN and DDD.
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The majority of patients with DDD have
circulating autoantibodies known as C3 nephritic
factor (C3NeF) that stabilize the alternative
pathway C3 convertase by conferring resistance
to factor H–mediated decay, thereby leading to
persistent complement activation.
Studies in C3 glomerulopathies have used
eculizumab for over a year in a number of
patients ,Herlits I,2012,Bomback As,2012.
Preliminary data is promising and may have
implications for many other diseases with
complement activation as a component.
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The humanized monoclonal anti-CD20 antibody
rituximab has been used as adjunctive therapy in an
attempt to deplete the B cells responsible for
producing C3NeF, but the results have thus far been
limited.
Bomback et al. (CJASN,2012), have conducted a pilot,
proof of concept study to assess the utility and safety
of eculizumab for the treatment of six patients with
either DDD or C3GN over a 1-year course.
In light of the poor performance of more traditional,
nonselective immunosuppressive therapies, the
ability of eculizumab to reverse clinical and
pathologic findings in these disorders is astounding.
ORAL GALACTOSE
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Savin et al. 2008, proved a high affinity of FSGS-PF
for galactose, based on chromatographic studies.
Galactose inactivates FSGS-PF and seems to lead to
its clearance from plasma.
In vivo administration of galactose has been
associated with a significant decrease in permeability
factor in a patient with FSGS-PF-associated nephrotic
syndrome, but with no improvement in proteinuria,
as the patient was already dialysis-dependent.
In another report, remission was achieved after
galactose therapy in an adult male with a nephrotic
syndrome that was resistant
to corticosteroids, other immunosuppression, and
plasmapheresis.
The patient was given oral galactose as a last resort
treatment, which was followed by a long-standing
remission of his nephrotic syndrome that correlated
with the reduction of FSGS-PF activity DeSamet E et
al, 2009.