Corticosteroid-Sparing Regimens in Renal Transplantation: An Expert
I thought those of you looking at transplants might find this
helpful.
Corticosteroid-Sparing Regimens in Renal Transplantation: An Expert
Interview With Herwig-Ulf Meier-Kriesche, MD
Editor’s Note:
Corticosteroids (steroids) have played a critical role in the
evolution of renal transplantation. The first transplants were
performed under azathioprine (AZA) monotherapy,[1] but with few long-
term survivors, investigators were prompted to design a better
regimen. In the early 1960s, it was discovered that AZA and
corticosteroids had additive and synergistic effects in renal
transplant recipients,[2] and by 1964, this approach became standard
therapy worldwide.[3-5] In modern immunosuppressive regimens, the
cornerstone agents are the calcineurin inhibitors cyclosporine and
tacrolimus; corticosteroids along with other agents such as
mycophenolate mofetil and sirolimus are considered adjunctive
agents. However, because of the significant morbidity and mortality
associated with chronic corticosteroid use, there has been a desire
to eliminate or at the very least minimize corticosteroid use in
transplant recipients. Initial attempts were met with increased
rates of acute rejection, but these newer and more potent adjunctive
agents may allow for safe and effective steroid avoidance or
withdrawal. Gwen Mayes, MMSc, JD, freelance medical writer,
interviewed Herwig-Ulf Meier-Kriesche, MD, Associate Professor of
Medicine, University of Florida College of Medicine; Clinical
Director of Renal Transplant, Shands Hospital at the University of
Florida in Gainesville, to discuss corticosteroid-sparing
immunosuppressive regimens in renal transplantation.
Medscape: Good morning, thank you for taking some time to speak with
Medscape today about steroid avoidance and withdrawal. Is it
possible to say which immunosuppressive regimen has the most
potential for successful steroid withdrawal?
Dr. Meier-Kriesche : I think you would have to rephrase the question
a little bit and say, which immunosuppressive protocols “at the
moment” have shown the feasibility or the possibility of safe
steroid avoidance as opposed to steroid withdrawal. The regimens
which probably have been most studied are CellCept (mycophenolate
mofetil [MMF]) combined with Prograf (tacrolimus [TAC]) and TAC
combined with rapamycin (sirolimus [SRL]); I think those are the
most frequently used regimens in addition to different induction
regimens. Most of the time, most centers use thymoglobulin (rabbit
antithymocyte globulin [rATG]), but some centers initially have also
used IL-2 receptor blockers as induction agents and more recently a
lot of centers are using Campath-1H (alemtuzumab). Dr. Dixon Kaufman
at Northwestern University switched about 1.5 years ago to
alemtuzumab induction. The largest experiences with steroid
avoidance protocols are at Northwestern University, the University
of Minnesota, and Drexel University College of Medicine/Hahnemann
University Hospital.
Medscape: You mentioned the role of induction therapy; how does that
play into these clinical trials?
Dr. Meier-Kriesche: I think in terms of any minimization or
withdrawal studies, induction therapy has become more and more
important. Clearly, induction therapy is efficacious in preventing
acute rejection early on and, especially in early minimization or
avoidance studies, additional immunosuppression is needed, and that
is why induction is so important in these trials, especially in
steroid avoidance trials because usually patients get quite large
doses of steroids early after transplantation, which are tapered
down relatively slowly. So, if you take that early coverage away,
you probably have to cover patients with something else and most
centers would give either rATG or alemtuzumab at this point.
You asked which regimen would be most successful and I said the ones
that have been most frequently used are MMF + TAC and SRL + TAC.
Data were presented at this meeting by Dr. Anil Kumar[6] comparing
these 2 regimens, suggesting that at a year there is similar renal
function with these 2 regimens. He randomized patients to these 2
regimens and found that there was similar [renal] function,
identical graft survival, and overall the biopsies looked very
similar. There was a similar amount of chronic allograft nephropathy
(CAN). But, when they looked at the most severe cases of CAN they
actually found a little bit more in the MMF + TAC group, which
according to Dr. Kumar would probably indicate that the SRL + TAC
regimen is the better one for steroid withdrawal.
Converse to those findings, all of the other studies, actually the
bulk of the evidence, suggests a slight edge of MMF + TAC over SRL +
TAC. Dr. Lorenzo Gallon[7] presented data from Northwestern
University from a 3-year randomized trial of SRL + TAC vs MMF + TAC
that showed that renal function significantly improved in patients
on MMF + TAC, but there were significant concerns about
nephrotoxicity in the group treated with SRL + TAC, and these
patients also had significantly worse graft survival. So those
studies are a bit contrasting.
And then, probably the largest series of steroid avoidance, which at
this point has 5-year follow-up, is at the University of Minnesota;
[8] that’s also a regimen based on MMF + TAC. That’s not a
randomized study and it’s not a controlled study, we just have the 5-
year follow-up data and not all of the patients have reached 5
years. Only a relatively limited group of patients have actually
reached 5 years at this point, but clearly this experience indicates
that [the patients] are doing fairly well. Their overall graft and
patient survival at 5 years is excellent, with the caveat that the
Minnesota population is probably a lower-risk population –
Caucasians, probably highly compliant, educated, less high-risk
racial mix — and so probably an easier population to transplant,
but clearly an indication that corticosteroid avoidance can work.
And again Minnesota has chosen this regimen with MMF + TAC for their
steroid avoidance protocol, so I think there’s a little bit of
evidence for both of these regimens. Steroid avoidance is probably
feasible with different regimens, but in terms of just numerical
evidence, maybe just because more people are using, MMF + TAC has a
slight edge over the SRL + TAC combination.
Medscape: What’s been the reaction of your colleagues here about
these studies that have been presented?
Dr. Meier-Kriesche: Many of my colleagues I have talked to have
significant concerns because this has been studied for a long time,
over and over again; steroid avoidance or actually steroid
withdrawal is not a new idea. We have seen early reports of
excellent results with steroid withdrawal, but then in the long-term
oftentimes these results just didn’t hold true. The first big
disappointment was the Sinclair study[9] from Canada now almost 15
years ago and it was with different immunosuppression, essentially
cyclosporine (CsA) monotherapy as opposed to CsA with steroids. They
showed early on (up to 3 years) excellent graft survival with no
problems at all. And then, when all the patients had completed 5
years follow-up (it took a long time to complete the study) they
found a very, very significant deleterious effect in the steroid
withdrawal patients, but [again] it took a long time to accumulate
this data. Since then, people have continued to try newer
immunosuppressants in different combinations with induction agents
in steroid withdrawal studies and oftentimes, again, the early
results look good. Then, either the long-term results never became
available (a lot of studies that get presented at this meeting are 1-
or 2-year follow-ups and often there is no long-term follow-up), so
often you don’t really know what will happen with those patients
long term.
But the sense is that steroid withdrawal oftentimes in the long-term
hasn’t worked, and that’s why now we have shifted to steroid
avoidance, because there’s some sense that patients who have been on
steroids for a long time just can’t be taken off because their
immune systems somehow get used to being on steroids and when you
take them off you get into trouble. So now the thinking is that
steroid avoidance — never exposing the immune system to chronic
steroids — might actually allow for doing without steroids. But
again, the feeling is that we might again see these very late
effects and this is possibly again a story of early success that may
not hold true in the long term.
On the other hand, there’s a lot of concern about patients staying
on steroids. There’s a long list of important side effects;
cardiovascular risk factors increase with steroids and there is the
risk of diabetes. A lot of the diabetes risk of immunosuppressive
protocols is actually not related to any of the other agents, but is
specifically related to the use of steroids. And then there are
really terrible effects like avascular necrosis resulting in the
need for hip replacement and also the cosmetic side effects that
factor into noncompliance. A lot of patients won’t tell you that
they are not taking medications; they just stop taking them because
of the side effects, and steroids are clearly the drugs with the
most important cosmetic side effects. So, there’s a long, long list
of just concerns about steroids and everybody would like to get rid
of them. But on the other hand, ultimately how well these patients
do is dependent on how long they keep their kidneys. So whatever you
do to jeopardize graft survival also jeopardizes the patient, as
these are competing risks. It jeopardizes the patient who has a
fracture and requires hospitalization. The mortality of graft loss
is extremely high and the mortality on dialysis is extremely high,
which is why even though the patients and the physicians advocate
for steroid withdrawal, the ultimate concern is graft survival. You
have to show excellent graft survival in order to justify
potentially improving quality of life and comorbidities.
Medscape: You’ve alluded in your comments about a high-risk
population; why are African-Americans in particular often excluded
from these trials and are there other vulnerable populations that
you have to be especially attentive to?
Dr. Meier-Kriesche: African-Americans are actually not specifically
excluded from these studies; it’s not ethical to exclude certain
populations when you write a study protocol, and the reason is to
protect minorities. Oftentimes, however, and this is a classic
example, it’s actually not so protective for these minorities. For
example, you do a study and include maybe 5% of African-Americans
because it corresponds with your demographics. If these African-
Americans have deleterious effects from a certain protocol you might
not be able to see it at all because you just don’t have the number
of patients you need to really get at the question of whether it’s
safe for them. African-Americans are intrinsically a high-risk
population for acute rejection but probably also for comorbidities
and noncompliance, so it’s very difficult to do steroid avoidance in
this population.
Several centers have specifically tried to do steroid avoidance in
African-Americans. Dr. Don Hricik,[10] from University Hospitals of
Cleveland, presented an abstract yesterday that showed deleterious
effects of steroid withdrawal after 3 months in African-Americans,
just because they are a high-risk population. It might have been due
to the fact that a lot of these patients were noncompliant (that was
actually his concern), but if you partially withdraw
immunosuppression in a population that is noncompliant, that clearly
leads to bad outcomes and, whatever the reason, early on it looked
great and right now it doesn’t look feasible.
On the other hand, Dr. Anil Kumar[11] presented data comparing
steroid avoidance in African-Americans and Caucasians, and African-
Americans had just as good outcomes as did Caucasians. Some people
argue that Dr. Hricik wasn’t successful because he tried steroid
withdrawal as opposed to avoidance. Dr. Kumar actually did protocol
biopsies at 1 month, 3 months, 1 year, and later, and found that
there was a significant increase in early subclinical rejection.
Subclinical rejection means that the patients didn’t have any
clinical symptoms of acute renal failure. But on biopsies they found
a lot of rejection in the African-American patients. Then they went
on to treat that rejection and in doing so got excellent graft
survival compared with Caucasians, essentially meaning that if you
want to do steroid avoidance in African-Americans you have to do
protocol biopsies, and that is a very difficult thing. Biopsies in
themselves can be risky. Clearly, there’s a risk of bleeding and
ultimately even graft loss in a low percentage. And then, if you
look at the typical population we see, we can’t do protocol biopsies
on everybody. So it’s again a question of the feasibility of the
protocol. The early results look very good, but how widely
applicable they are to the African-American renal transplant
population with the need to do early protocol biopsies, I don’t
really know. And then again, we don’t know what the long-term data
will tell us.
Medscape: Are there similar concerns for children, for the pediatric
population?
Dr. Meier-Kriesche: Children are considered a high-risk population
for acute rejection and also for noncompliance, so there are very
significant concerns about steroid avoidance and steroid withdrawal
in children, very similar to that in African-Americans. The concerns
are similar because the numbers are low; it’s very difficult to get
adequate numbers to have the power to draw conclusions from these
studies. And, there is the important issue of noncompliance.
The less medications you have a transplant patient on, the greater
the chance that something might go wrong because compliance is not
an all-or-nothing phenomenon. They might skip 1 drug every once in a
while or they might skip another drug every once in a while.
Therefore, if they’re on more drugs there’s actually a better chance
that they’re going to be covered in some way. On the flip side, in
children the most important side effect is growth retardation and
that’s a huge concern. And so in children I think there is a bigger
push and greater justification for steroid avoidance. If we could
keep children with a kidney transplant off steroids, that would be
really wonderful because it would allow normal development and a lot
of the noncompliance we see in kids (even more so than in adults)
related to cosmetic side effects would be avoided. If children,
especially teenagers, don’t take their medications more often than
adults, it’s due to the acne and skin changes and general body shape
changes that are associated with steroids. If we could do without
steroids in children, I think it would be a significant advance.
There’s a good body of evidence (early results mostly with
daclizumab induction) that is relatively promising, but I would be
very careful about what that means in the long term and wait to see
if all our regimens really allow us to maintain people off steroids
long term.
Medscape: Another population we’ve heard a lot about here is the
aging population and the dramatic increase in individuals over 50
now on the waiting list. Do we know anything about how age factors
into this?
Dr. Meier-Kriesche: The elderly supposedly have a little bit lower
risk for acute rejection because of the aging immune system. On
average you would probably find in a transplant population that the
elderly reject less, but clinical experience teaches us that elderly
patients can actually have very bad rejection episodes. Combine that
with the policy by some of giving older and more marginal kidneys to
elderly recipients (which in part is patient choice because elderly
patients on dialysis don’t do very well) because they have
relatively less time to wait. If you think about it, a waiting time
of 3 years is not that long for a 20-year-old patient, but if you’re
70 years old and have a 3-year waiting time, you might never make it
to transplant. So older patients are clearly more accepting of more
marginal kidneys and, in fact, that’s what’s happening. Older
patients are getting kidneys from older and lower-quality donors.
Thus, intrinsically they have less nephron mass and less renal
reserve. When an older patient with a relatively less-functioning
graft has a rejection episode, they might lose a lot as opposed to
what would happen if they received an excellent graft (ie, a living-
donor kidney), where a little bit of a rejection probably would not
have a big impact.
But, an acute rejection episode can have a very significant impact
in a very marginal kidney. Early on there was some thought that it
would be easier to minimize immunosuppression (ie, steroid
withdrawal and avoidance) in elderly patients, but I think the
clinical reality with the use of more marginal kidneys is that in
the end the elderly reject and they can have very bad rejection.
It’s just that on average they have a little bit less frequent
rejection, so I don’t really think they differ all that much and
it’s not all that much easier to withdraw or avoid steroids in the
elderly.
Medscape: What does the evidence suggest regarding early vs late
withdrawal?
Dr. Meier-Kriesche: We have talked about that a little bit before.
Historically, all the studies have been steroid withdrawal studies.
The Sinclair study we talked about before was a steroid withdrawal
study and, subsequently, all the approaches have been steroid
withdrawal after 1 year, 6 months, or 3 months. The latest Hricik
experience[10] was steroid withdrawal after 3 months; that was the
study in African-Americans. People have tried to do shorter and
shorter steroid exposure, but over time these studies have been very
disappointing and that’s why now we have switched to steroid
avoidance, trying not to give steroids at all in order to get away
from this need to withdraw then because there might be just
something about chronic steroid exposure and the immune system that
makes it very difficult to get rid of steroids once you have been on
them long term. I think right now there’s agreement within the
transplant community that if you want to do away with steroids, you
really should be doing steroid avoidance as opposed to
corticosteroid withdrawal.
Medscape: You touched upon many of the side effects of steroids as
motivation for avoiding steroids. Is there an economic factor that
comes into play?
Dr. Meier-Kriesche: There are several economic factors. The side
effects of steroids — hypertension, diabetes, avascular necrosis,
and cataracts, and the consequent need for hospitalization and loss
of workforce productivity (due to sick days) — are very important,
and these are very expensive side effects. Treatment of these side
effects requires quite a bit of resources, so if you could do away
with steroids and prevent those side effects, we could ultimately
make transplantation cheaper. But the reality is that we are not
just doing away with steroids, but we are also adding induction
therapy and the sense in most centers is that we actually have to
increase the exposure to the other drugs in order to avoid steroids.
And those drugs are also not without side effects. For example, when
you switch to a more intense immunosuppressive regimen just to do
away with the steroids, you might run into problems such as
polyomavirus (BK) nephropathy. Corticosteroids in themselves
probably have no facilitating effect or impact on BK virus
nephropathy; on the other hand, all the other immunosuppressants
increase the risk of BK virus nephropathy, so the net amount of
drugs that put you at risk for BK virus nephropathy probably
increases in steroid-free regimens. By doing away with one set of
problems, you might run into totally different problems.
BK virus nephropathy has become a very prevalent problem in the last
5-6 years. It’s associated a lot with graft loss and some people
believe that all the improvements we have made in terms of reducing
acute rejection and improving renal function have really not been
followed by comparable improvement in graft survival because we are
buying into infectious complications down the line and BK virus
nephropathy is one of the reasons why we are losing grafts, despite
having decreased the rate of acute rejection.
But yes, if ultimately safe, avoiding steroids could potentially
have great health and economic impacts if you think about the
associated cardiovascular risk factors. If steroid avoidance really
decreased cardiovascular morbidity and mortality, there would be a
huge health economic impact, but we might be also buying into a
different set of problems. And again the caveat, if ultimately you
have more graft loss, that’s probably the biggest ticket item in
terms of health economics because that costs the most money when a
patient goes back on dialysis. And Dr. Schnitzler[12] showed in one
of the sessions here that the number of dollars associated with
going back on dialysis is huge, and so we just have to balance these
things and I really think we’re going to have to see from future
studies what ultimately turns up.
Medscape: What will you look forward to hearing about next year at
this meeting regarding steroid-sparing regimens?
Dr. Meier-Kriesche: I really think that it is important to hear
about the same studies again and see what the longer-term follow-up
data show. For example, Dr. Matas now has 5-year follow-up data, but
only about 30 or 40 patients have reached 5 years. Next year,
another 50 or 80 or even 100 patients may reach that end point, so
the data are going to be more robust. And I think that the key to
all these studies is longer-term follow-up and protocol biopsies as
an end point.
I don’t think I’ve mentioned before a very important study that was
presented yesterday in which they actually randomized to start
avoidance as opposed to a low-dose steroid maintenance.[13] They did
protocol biopsies at 1 year and found a significant increase in
fibrosis in the steroid avoidance patients as opposed to the
patients who had been maintained on very low-dose steroids. They
used a very standard steroid avoidance approach with rATG induction
and 7 days of steroids and then TAC and MMF as maintenance
immunosuppression, which is probably the steroid avoidance regimen
which is most frequently used. It’s very concerning that they found
a significant difference in the histology of the kidneys at a year.
They didn’t see anything in terms of renal function or graft
survival, and that’s what all the studies show. But the biopsies
clearly showed structural changes with fibrosis and CAN, which
probably indicates that doing away with steroids could be risky in
the long term. Studies are needed in which we don’t look just at the
very crude markers of renal function and graft survival, but also at
biopsy markers and potentially even molecular markers in order to
see if these strategies are really working. That’s what I believe is
going to come out over the next 5 years.
Medscape: Thank you for your time.
Dr. Meier-Kriesche: Thank you very much.
References
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Related Links
Online CME Articles
Corticosteroid-Sparing Immunosuppression in Renal Transplantation
Funding Information
Supported by an independent educational grant from Astellas
Herwig-Ulf Meier-Kriesche, MD , Associate Professor of Medicine,
University of Florida College of Medicine; Shands Hospital at the
University of Florida
Disclosure: Gwen Mayes, JD, MMSc, has disclosed no relevant
financial relationships.
Disclosure: Herwig-Ulf Meier-Kriesche, MD, has disclosed that he has
received grants for clinical research from Novartis, Roche, and
Fujisawa/Astellas. Dr. Meier-Kriesche has also disclosed that he has
received grants for educational activities from Novartis, Roche, and
Fujisawa/Astellas. Dr. Meier-Kriesche has also disclosed that he has
served as an advisor or consultant to Novartis, Roche,
Fujisawa/Astellas, and Prosanos.