Renal transplantation is the modality of choice for renal replacement therapy in patients with end-stage
renal disease. Following induction immunosuppression, most maintenance immunosuppressive regimens
include a calcineurin inhibitor. While this class of immunosuppressive therapy is highly effective it has a
toxic effect on the renal allograft termed calcineurin inhibitor toxicity which can contribute to graft loss
over time. Thus, their minimization, withdrawal or avoidance is of interest to transplant clinicians as well
to renal transplant recipients. This mini review takes an in-depth review and analysis of all published
data in this field.
For patients with end stage renal disease (ESRD) renal transplantation offers the best
survival advantage compared to other modalities of renal replacement therapy . After
pairing of the donor and recipient and immunological risk is ascertained the next step in renal
transplantation is immunosuppression. Immunosuppression is done in two stages; induction
followed by maintenance immunosuppression. The induction phase is where intense
immunosuppressive agents are administered at the very onset of transplantation to minimize
the burden of acute allograft rejection. Protocols are not standard across all transplant units
as optimal induction immunosuppression therapy remains controversial [2,3]. However, it
can broadly be classified into two strategies. The first one is based on the use of significant
doses of standard immunosuppressive therapy (a calcineurin inhibitor, an antimetabolite
and glucocorticoids). The other strategy employs antibodies targeted at T-cells in addition to
standard immunosuppressive therapy. The choice of agent is based on the recipient’s risk of
developing acute rejection. Gebel et al.  stratified the prospective renal transplant patients
into various categories according to immunological risk in renal transplantations. Based on
this with further additions the principles of risk assessment are as follows:
a. High Immunological risk: During transplant high titers of circulating antibodies
targeting mismatched donor HLA also known as donor-specific antibodies are present.
This can lead to hyperacute rejection. The presence of DSA precludes transplantation.
However, there are reports of innovative pre-transplant desensitisation regimens to
reduce this risk.
b. Intermediate immunological risk: The low titer of DSA at the time of transplantation
and historic DSA is not detectable. It may be acceptable to consider intensified
immunosuppression as well as immunological monitoring in the post-transplant period
c. Standard immunological risk: Where there is no evidence of donor-directed
sensitization to HLA.
It is worth noting that recipients of a renal allograft who
currently have a functioning solid-organ transplant (such as heart,
lung or liver) and are on maintenance immunosuppression are
often spared from induction immunosuppression. However, this
is not the standard in all centers, and some still prefer some form
of induction agent . Recipients of two haplotype identical living
related kidneys who are Caucasian have a significantly low risk of
acute rejection and do not require induction therapy .
Standard immunosuppressive therapy for maintenance
immunosuppression entails a calcineurin inhibitor, an
antimetabolite and a glucocorticoid. Since the advent of calcineurin
inhibitors (CNIs) in the 1980s; short and intermediate-term
allograft survival had improved. However, post-transplant graft
failure rate beyond ten years has remained unaffected . The
two leading causes of late renal allograft loss are chronic allograft
nephropathy (CAN) and death with a functioning graft (DFG).
Cardiovascular disease and malignancy are attributed as the
primary causes of DFG. The underlying pathogenesis of CAN
is not entirely understood. It which manifests histologically as
interstitial fibrosis and tubular atrophy. Both immunological and
non-immunological elements have been identified as causes of CAN
[8,9]. Chronic CNI exposure has been recognized as a risk factor
for CAN . Treatment regimens have therefore focused to either
minimize their use or to avoid them completely, however, this
strategy has proven to be quite disappointing due to the resultant
increase in rates of acute rejection [11-14]. Apart from the resultant
allograft associated complications, CNI use has been associated
with the development of new-onset diabetes after transplantation
(NODAT), hyperlipidemia and hypertension [15,16]. In an attempt
to move away from CNIs there has been significant focus on the
employment of mammalian target of rapamycin inhibitors (mTORi)
like everolimus and sirolimus in renal transplantation [17,18].
Given the potential harm to both recipient and allograft from
long term CNI exposure, several RCTs were conducted to test
strategies to minimize exposure. Minimization is carried out by
lowering the target blood levels which are routinely done to titrate
dosing. Minimization of CNI target blood levels has been tested
for both (Ciclosporin) CsA and (Tacrolimus) TAC. Minimization
has also been tried with several combinations of induction agents
and other immunosuppressive drugs. A total of 36 RCTs (Table
1) were conducted so far evaluating CNI minimization . CsA
minimization alone was studied in 22 RCTs and TAC alone in seven
studies. Seven other studies pooled groups that received TAC or
CsA. Mycophenolate is both its formulations were used as the main
combination immunosuppressive agent in 19 studies. mTORi in
combination with CNI were evaluated in 14 studies. Two studies had
multiple therapies including CNI, mTORi, MMF and AZA. Vathsala
et al.  evaluated a single agent CsA without an antimetabolite.
Nearly all studies used a steroid (prednisone) in both intervention
and control arm. Induction therapy was used in most of these
trials except two of them, and eleven other studies did not report
on induction. Basiliximab was the most employed induction agent
used most of them. Three of them used daclizumab, two used rATG
and one used alemtuzumab. In one study, the induction therapy
was not uniform and followed local protocol. 29 studies had begun
CNI minimization within the first six months post-transplantation,
three of them delayed the process till six months had elapsed and
four postponed until one year.
Table 1: CNI minimization studies.
Three measures of outcome were renal allograft function, the
risk of BPAR and graft loss. Combinations with MMF and lowdose
CsA have better results for all three measures as mentioned
above compared with standard-dose CsA. With MMF and TAC,
there is a sizeable benefit for renal function, but current evidence
fails to make conclusions for the other outcomes. Combinations
with mTORi and low-dose CsA revealed better renal function but
no difference in BPAR compared to standard-dose regimens. Data
for mTORi with TAC are scarce. Basiliximab induction with mTORi
and low dose CNIs is associated with better renal allograft function
but no difference in the risk of BPAR and graft loss. The evidence
is too little to conclude the combination of basiliximab induction
with MMF. CNI minimization started within the first six months
post-transplantation in MMF combination is linked to improved
allograft function, lowered BPAR, infection and graft loss compared
to standard-dose combinations. However, minimization postponed
to after six months or later of transplantation has been linked with
greater rates of acute rejection. The Symphony trial compared four
treatment protocols [16,21].
a) No induction followed by standard-dose CsA, MMF and
b) Daclizumab induction followed by low-dose CsA, MMF
c) Daclizumab induction followed by low-dose TAC, MMF
d) Daclizumab induction followed by low dose sirolimus,
MMF and corticosteroids.
Daclizumab induction followed by low-dose tacrolimus, 2g
of MMF and corticosteroids had the most favorable results with
better renal allograft function, lower incidence of BPAR and rate
of graft loss. The Campath (alemtuzumab), CNI reduction and CAN
(3C) study is an open label, multicenter randomized controlled trial that aimed to answer two key questions. First to evaluate
outcomes between campath (alemtuzumab) versus basiliximab
induction for renal transplant recipients. Those receiving
alemtuzumab will have low-dose TAC, MMF and no steroids, while
those receiving basiliximab will have standard dose TAC, MMF and
steroids. It includes most categories of patients eligible for renal
transplantation. These include previously transplanted patients,
those receiving a deceased or living donor kidney as well as those
who are highly sensitized. Secondly, after six months of maintenance
with immunosuppression with TAC based immunosuppression,
they will be re-randomized to either stay on TAC for long term or
switched to SRL based maintenance immunosuppression as a CNI
minimization strategy . 7% of 426 renal transplant recipients
who received alemtuzumab had one occurrence of biopsy-proven
acute rejection (BPAR) in the first six months post-transplantation.
At the same time, 16% of those who received basiliximab had
an episode of BPAR. This corresponds to a 58% reduction with
alemtuzumab induction. The study is an ongoing and long-term
follow-up with determining if these initial findings would translate
to better transplant outcomes .
As discussed previously CNI minimization has proven to be of
benefit. Studies have been conducted to evaluate if recipients with
a CNI based regimen could benefit by having the CNI withdrawn
while continuing on alternative immunosuppressive drugs. To date,
15 randomised control trials (Table 2) have evaluated CNI withdrawal.
MMF was included as a primary alternative to CNI in nine of
them and mTORi in six of them. In ten studies CsA was withdrawn,
four with EVR or SRL and six with MMF. In two studies TAC was
withdrawn with SRL used. In three of the studies, MMF was used
with combined data for those on CsA or TAC. Nine of them initiated
CNI withdrawal within six months’ post-transplant while five studies
withdrew CNI after six months or longer after transplantation
[67-72]. In conclusion, these studies revealed that CNI withdrawal
is linked with a greater risk of BPAR for patients on mycophenolate
acid formulations or mTORi compared to those on combination
therapy with a CNI plus adjunctive therapy. Where CNI was withdrawn
from patients continuing on MMF the risk of graft loss was
higher as compared to those on combination CNI and MMF. Continuing
on MMF after CNI withdrawal, however, was linked to improved
renal function compared to combination therapy with a CNI.
Table 2: CNI withdrawal studies.
Early vs. late CNI withdrawal
When assessing the timing of CNI withdrawal, three studies
began CNI withdrawal within the first six months after transplantation,
and this is termed ‘early withdrawal’, and five studies began
CNI withdrawal six months or later post-transplantation termed
‘late withdrawal’. Early withdrawal revealed an increased risk of
graft loss and death and the evidence was inconclusive for BPAR
and allograft function. The ZEUS trial  investigated 300 de novo
renal transplant recipients randomized to remain on CsA or switch
to everolimus at four and a half months into the post-transplant period.
This early withdrawal of CNI was associated with improved
renal function with follow-up up to 5 years, and the resultant increase
in mild BPAR did not impact long term allograft function.
Similar results have been reported in the HERAKLES study .
The CONCEPT study  evaluated the conversion from CsA to SRL
3 months post-transplant. All patients also received MMF and oral
steroids which were to discontinue at eight months. The conversion
of CsA to SRL 90 days’ post-transplant combined with MMF was associated
with improved renal allograft function. In the CONVERT
trial  renal transplant recipient on CsA or TAC were randomly
assigned to either continue on the CNI or convert to SRL from CNI.
This showed that at two years in patients who were converted to
SRL had promising graft and patient survival with no significant difference
in BPAR. Importantly it revealed a lower incidence of malignancy
as compared to continuation of CNI therapy. In other studies,
with late withdrawal, there was a greater risk of BPAR on maintenance
MMF post-CNI withdrawal; there wasn’t enough evidence to
support any conclusion on infection outcomes in these subgroups.
As with strategies employing conversion, induction therapy was
not expected to have any clinically significant impact during the later
period when most studies initiated CNI withdrawal .
Given the degree of CNI-associated toxicity, studies were also
done to assess if they could be completely avoided. To date nine
RCT’s have looked at immunosuppressive protocols which are CNI
free and were based on SRL or belatacept (table 3). SRL was alone
in one study, in combination with AZA in another and finally with
MMF in 5 of them. BENEFIT  and BENEFIT-EXT study  were
two large scale multinational trials that compared belatacept and
MMF to CsA and MMF after BAS induction for both groups. Only
expanded criteria donors were enrolled in the BENEFIT-EXT study
as these were associated with suboptimal clinical outcomes. Strong
and less intensive treatment regimens for belatacept was compared
in both BENEFIT studies. The ORION trial  looked at the safety
and efficacy of SRL. Recipients of renal transplantation were
randomised to three groups:
A. Group 1 - SRL and TAC with the elimination of TAC at
B. Group 2 - SRL and MMF
C. Group 3 - TAC and MMF
Group 2 resulted in greater than expected BPAR and so was
terminated early on. The study concluded that SRL based failed to
show improved outcomes for renal transplant recipients. Given the
available data, it is difficult to conclude if CNI avoidance regimes
are successful as these studies resulted in inconclusive results and
included small patient numbers (Table 3). Furthermore, a uniform
recommendation could not be drawn as the immunosuppressive
therapeutic regimes, and induction agents in individual studies
were heterogeneous. There was no difference in death or graft
loss when belatacept was compared to CsA however belatacept
was associated with better renal parameters [79-83]. CNI-free
studies where mTORi and MMF were used revealed improved renal
function, but the risk of graft loss was greater when compared to
tacrolimus-based regimens. When compared to CsA regimens there
was no difference in the risk of graft loss .
With a lot of conflicting study results, the optimal
immunosuppressive regimen remains controversial. Recipients of a
renal allograft should have induction immunosuppressive therapy
that consists of an antibody (rATG, basiliximab or alemtuzumab)
plus maintenance immunosuppressive therapy (tacrolimus,
mycophenolate mofetil or azathioprine and glucocorticoids)
rather than maintenance immunosuppressive therapy alone .
Considering all the published data in the 36 trials focusing on
CNI minimisation, it revealed that compared to standard dose
immunosuppression, early minimization of CNI was clearly
associated with positive outcomes - better renal function, lowered
risk of BPAR and graft loss.
There was also a lower incidence of opportunistic infections in
the immunocompromised host including a lower CMV incidence.
BK virus infection was an exception as the evidence proved to
be inconclusive. There was no difference observed amongst
the different regimens for patient death . CNI withdrawal
was associated with a greater risk of BPAR for patients on
mycophenolate acid formulations or mTORi compared to those on
combination therapy with a CNI plus adjunctive therapy. Where CNI
was replaced with mTORi studies have revealed that at two years in
patients who were converted to SRL, there was promising graft and
patient survival with no significant difference in BPAR. Importantly
it revealed a lower incidence of malignancy as compared to
continuation of CNI therapy. Given the literature, it is challenging to
conclude if CNI avoidance regimes are successful as current studies
had small patient numbers and moreover revealed inconclusive
results, however, CNI minimization has a positive effect and should
joudioulsy be reduced over time.
Leas BF, Uhl S, Sawinski DL, Clark J, Tuteja S, et al. (2016) AHRQ comparative effectiveness reviews. Calcineurin inhibitors for renal transplant, Agency for Healthcare Research and Quality, Rockville, Maryland, USA.
Budde K (2015) Month 48 follow-up results of the HERAKLES study: superior renal function after early conversion to an everolimus-based calcineurin free regiman. Journal of the American Society of Nephrology, pp. 26:76.
Professor, Chief Doctor, Director of Department of Pediatric Surgery, Associate Director of Department of Surgery, Doctoral Supervisor Tongji hospital, Tongji medical college, Huazhong University of Science and Technology