IV. Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial
- In your own words, summarise this article.
- What are the weakness and strength of this study?
- Compare conclusion of the short-term with long-term study.
- How will the 3C study influence your practice?
3 C study ;done in 6 months following transplantation ,was a pragmatic RCT of sequential randomization between induction therapy using alemtuzumab and basiliximab; and between Tac and sirolimus as maintenance therapy.
It was found that sirolimus maintenance therapy did not improve graft function with increased risk of rejection. eGFR was comparable in induction groups.
Limitations of the study include being open label,6 month duration and involvement of relative small number from participants, but it has the advantage of linking national registries
strength:
a randomized , multi- center study. – large patient size.
weakness:
not double blind study- no adherence to medication
short term: no difference in rejection among both arms.
long term, there was significant less biopsy documented rejection in the almetuzumab arm. however, there was no difference in graft function or infection in both arms.
Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial
It is a double blind RCT, assessing the efficacy of Tacrolimus in comparison to Sirolimus as a maintenance therapy after 6 months of tacrolimus. Induction therapy will be either Alemtuzumab or Basiliximab from first 3C study.
The primary outcome is to assess the eGFR at 18 months after maintenance therapy on tacrolimus in comparison to Sirolimus.
A total of 394 patients out of 852 patients were randomized into 2 arms (tacrolimus and sirolimus). They were followed up to 18 months post-randomization, eGFR was calculated using MDRD equation.
Compliance in sirolimus group reduced to less than half, 48% at 18 months, while it was 94% in the tacrolimus group. There was no significant effect of choices of induction therapy on eGFR at 18 months.
The sirolimus group was associated with significantly increased risk of BPAR (14.7% vs 3%). It was also associated with increased risk of any serious infection as well as non-opportunistic infections, including respiratory and gastrointestinal infections. There was a significantly increased association of anaemia, proteinuria, elevated serum cholesterol and triglycerides in the sirolimus group.
A non-significant increase in non HDL levels and post transplant diabetes mellitus (PTDM) was observed in sirolimus group. There was no significant difference with respect to transplant failure, malignancy or mortality.
Conversion of CNI to mTOR inhibitors post-transplant is associated with poor adherence, does not improve graft function and is associated with increased risk of rejection and serious infections.
2. What are the weakness and strength of this study?
Weaknesses:
Open-label trial initial period of study but later it had been double blinded
Only 48% of original study population underwent randomization at 6 months post-transplant
DSA not measured in the trial
Low adherence in sirolimus group
Strengths:
The long term study on conversion of tacrolimus to sirolimus is a double blind RCT
Largest study of its kind to assess the conversion of tacrolimus to sirolimus as previous study assess cyclosporine
Bold decision to continue on long term with conversion to mTORi
Elective conversion to sirolimus-based maintenance therapy does not improve transplant function 18 months later no matter which induction protocol, and is associated with significant risk of rejection and infection.
How will the 3C study influence your practice?
Sirolimus still have mammoth task to convince as maintenance therapy over tacrolimus. I would still prefer tacrolimus as maintenance therapy.
This is a RCT comparing two different immunosuppressant protocol on eGFR at 18 month post-kidney-transplantation. Induction therapy was randomly allocated to receive alemtuzumab or basiliximab and then the first 6 month maintenance therapy with tacrolimus, MMF (and prednisolone if in basiliximab group) was starts. After that patients who were eligible were randomized in two groups: sirolimus based or Tacrolimus based maintenance therapy. A 3 months after this randomization 76% in sirolimus group vs 99% in Tac-group and at 18 months 48% vs 94% remained adherent to their randomization, respectively. Reasons for stopping allocated therapy were rejection (6%) and infection (4%).
Mean eGFR at 18 months later were 53.7 compared to 54.6 ml/min/1.73m^2 for R Sirolimus and Tacrolimus-based groups, respectively and this was not different between two induction therapy groups. Rate of rejection was lower in Tacrolimus group. Sirolimus had no effect on cancer or mortality, NODAT or vascular events but anemia and proteinuria and hyperlipidemia were more prevalent. In conclusion conversation to sirolimus-based maintenance immunosuppression protocol 6 month after kidney TX was not associated with better outcome.
The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months post-transplantation.
The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus-based and 197 to tacrolimus-based therapy.
Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m2 in the tacrolimus group (P = .50). Biopsy-proven acute rejection
(29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus-based therapy, sirolimus-based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection.
Introduction
Calcineurin inhibitors (CNIs, eg, tacrolimus) are central to modern immunosuppression but are associated with graft fibrosis and atrophy, worsening transplant function, and long-term transplant failure.
Immunosuppression strategies that minimize CNI exposure may be expected, therefore, to reduce the rate of late transplant failure.
Inhibitors of the mammalian target of rapamycin pathway (mTORi, eg, sirolimus) were first tested in various strategies to replace CNI; however, de novo use (ie, from the time of transplantation) is associated with complications, and a large trial of late (ie, >6 months
post-transplantation) conversion from CNI-based therapy found no improvement in subsequent function.7 In contrast, early (ie, within 6 months of transplantation) conversion to mTORi has been shown in some (but not all) trials to improve transplant function compared with remaining on cyclosporine-based immunosuppression.
Another potential benefit of conversion to mTORi is a reduction in the risk of malignancy post-transplantation (especially skin cancer). However, a recent meta-analysis suggested that sirolimus may be associated with an increased risk of all-cause mortality.
mTORi have more favorable effects than CNIs on tolerogenic T regulatory cells, and this effect may be most notable after alemtuzumab-based induction therapy.
DISCUSSION
The 3C Study was set up to investigate whether it is feasible to establish patients on long-term CNI-free immunosuppression and whether this is associated with reduced graft attrition (using kidney function [eGFR] as a surrogate in this analysis). Based on previous work, we hypothesized that the use of alemtuzumab-based induction therapy might enable patients to be established on sirolimus based therapy without the complications (wound healing, rejection,
mouth ulceration, pneumonitis) that have limited such strategies previously.
Our findings suggest that elective conversion to sirolimus at about 6 months after kidney transplantation does not improve subsequent transplant function and carries significant risks of rejection and infection.
Strength
It contained a wide range of various types of participants.
Weakness:
Only about half of the recipients enrolled at the time of transplantation entered the comparison
Non-adherence
They don’t monitor the DSA
3C study was the need for it to be open-label.
Only 18 months period of followup
Actually this study will not change our practice in our center
-Studies show a combination of alemtuzumab induction and conversion of CNI to sirolimus 6 months later of transplant have a good result.
– It is a continuation of short term 3C study. Details of 3C study reported in Q 3.
— 394 participants in this study.
-Study is compared sirolimus versus tacrolimus-based maintenance therapy.
-recipient with functioning graft between 5-7months after transplantation allows to participate in this comparison with 2 exclusion criteria:
1. A proven rejection episode in the previous month.
2.Proteinuria ˃800mg/day.
-All patients received MMF and prednisolone if considered necessary by the managing clinician.
-There are high rejections and infections in sirolimus-based therapy in the first 6 months.
-After 18 months no difference in eGFR and baseline proteinuria between 2groups.
– No evidence that sirolimus-based maintenance therapy was more effective after alemtuzumab-based than basiliximab-based induction therapy
-Sirolimus induced proteinuria .
–Strength of this study:
randomized .multicenter study.
Weakness of study:
Less than half of the participants recruited at the time of transplantation entered this study.
Information on concomitant immunosuppression and reason for stopping was collected for only 6 months after randomization.
It is a requirement to be open-label
-In a short-term3C study, alemtuzumab–based induction treatment followed by CNI reduction and low dose MMF and steroid can reduce the risk of acute rejection in the first 6 months after transplantation.
-In long –term 3C study, Findings suggest that compared with continuation of a tacrolimus-based regimen, elective conversion to sirolimus-based maintenance therapy doesn’t improve transplant function 18 months later and is associated with rejection and infection
-I preferred to use alemtuzumab as an induction therapy according to these studies.
Calcineurin inhibitors are central to modern immunosuppression but are associated with
graft fibrosis and atrophy, worsening transplant function, and long-term transplant failure.
Immunosuppression strategies that minimize CNI exposure may be expected, therefore,
to reduce the rate of late transplant failure.
In the current report, the results of the Sirolimus- versus tacrolimus-based maintenance
therapy randomization are presented.
Induction therapy was randomly allocated (either Alemtuzumab or basiliximab based),
and all participants received tacrolimus and mycophenolate (and prednisolone if
assigned basiliximab). Participants with a functioning transplant between 5 and 7 months
after transplantation were eligible to participate in this comparison of tacrolimus- versus
Sirolimus-based maintenance therapy.
Patients were randomized equally to either
(i) Sirolimus based maintenance therapy (immediate cessation of tacrolimus
and Sirolimus started on next day: 3 mg daily [or 2 mg if weight less than 50mg. target
trough concentration 6-12 ng/mL for the first 6 months, thereafter 5-10 ng/mL)
or (ii) tacrolimus-based maintenance therapy (target trough concentration 5-7 ng/mL).
All participants also received mycophenolate and prednisolone if considered necessary
by the managing clinician.
Study finding dings suggest that elective conversion to Sirolimus at about 6 months after
kidney transplantation does not improve subsequent transplant function and carries
significant risks of rejection and infection.
What are the weakness and strength of this study?
limitation of the 3C Study was the requirement for it to be open label.
under half of all participants recruited at the time of transplantation entered this
comparison.
Reason for stopping were collected for only 6 months after randomization.
Poor compliance with Sirolimus group.
Compare conclusion of the short-term with long-term study:
Finding in short study i.e. in the first 6month , suggest that Alemtuzumab-based
induction treatment (i.e., Alemtuzumab followed by reduced CNI treatment, low dose
mycophenolate, and steroid avoidance) roughly halves the risk of acute rejection in the
first 6 months after transplantation compared with standard basiliximab-based induction
treatment.
In long term study there’s no proved benefit of Sirolimus over TAC in reduce late AR.
How will the 3C study influence your practice?
We continue our practice of using TAC on maintenance therapy ,and consider low dose TAC as effective long term maintenance therapy.
This is a continuation of the short term 3C study .
They studied the possibility of shifting to sirolimus following alemtuzumab induction therapy .
Out of 852 patients , 394 were randomized to receive sirolimus based IS , after 3 months of maintenance ttt , only 148 remained on sirolimus and the shift was attributed to rejection and infection episodes and the no reached 91 patient by 18 months .
They concluded that the shift to sirolimus is associated with increased risk of acute rejections, even in patients receiving alemtuzumab as induction
Strengthes of the study include
Multicenter study with longer follow up
its considered the largest trial for CNI avoidance .
1st large trial to compare tacrolimus to serolimus
Weaknesses include only less than half of the patients recruited at the beginning of the trial , remained on sirolimus
Another weakness is that its an open label trial
Short term 3C concluded that alemtuzumab as induction therapy can allow using lower doses of CNI ,MMF with steroid avoidance, without risking acute rejections, up to 6 month post transplant.
Long term 3C study studied the possibility of shifting to sirolimus in patients receiving alemtuzumab as induction and they concluded that it was associated with adverse outcomes compared to tacrolimus based treatments .
In our center there is no alemtuzumab, shifting to sirolimus is related to CNI sever toxicities ( TMA , nephrotoxicity) and malignancies
This 3C study was conducted to evaluate long term outcom in renal transplant recipients on CNI based IS versus those on MTOR inhibitors.
CNIs reduce short-term kidney transplant failure, but was associated chronic nephrotoxicity and late transplant loss.
The 3C Study was a randomized controlled trial of sequential randomizations between alemtuzumab and basi-liximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation.
The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy.
It was found that sirolimus group had no significant effect on eGFR at 18 months,with more Biopsy-proven acute rejection and higher incidence of serious infections defined as opportunistic infections or required hospitalizations in sirolimus group .
Sirolimus group showed significant increase of; anemia,
elevated serum cholesterol and triglycerides DM .
There was higher incidence of proteinuria mechanism of sirolimus-induced proteinuria is unclear,but proteinuria is a recognized risk factor for subsequent transplant failure.
This study observed no significant effect on major vascular events or all-cause mortality, but with only 23 and 20 such events, respectively, the study’s power was negligible.
A recent meta-analysis has suggested that sirolimus is associated with an increased risk of death.However, this effect was only marginally statistically significant in unadjusted analyses .
Sirolimus group also showd more non adherence at 18 months than tacrolimus group due to higher risks of infection and rejection.
The study shows no significant difference between both grops with graft failure, malignancy may be due to short time of the study.
Early use of mTORi in the first 6 months posttransplantation was associated with complications,while late use after 6 months posttransplantation with conversion from CNI-based therapy showed no better outcomes.
In a recent meta-analysis sirolimus found to associated with an increased risk of all-cause mortality.
In Conclusion
study concluded that conversion of CNI to mTOR inhibitors post-transplant is associated with poor adherence, does not improve graft function and is associated with increased risk of rejection and serious infections.
2. What are the weakness and strength of this study?
Strengths of the study
– randomized trial
– included recipients from different centers
-Although these analyses were based only on 18-month follow-up, the 3C Study has established linkage with appropriate national registries, so longer-term follow-up will be conducted in a cost-effective manner and may yield informative results.
-the primary outcome eGFR at 18 months after randomization was collected by linkage with the UK Renal Registry, which collects its data through routine extraction from hospital databases, making it highly unlikely that the values entered would be biased with respect to treatment allocation.
Limitations of the study
-under half of all participants recruited at the time of transplantation entered this comparison.
-open label study
-Low adherence in sirolimus group which might have affected graft function
-short time of the study to assess malignancy risk
– they didn’t measure DSA n both groups
Compare conclusion of the short-term with long-term study.
Short term study concluded that
Induction with alemtuzumab allowed reduction of CNI dose and has reduced incidence of rejection in the first 6 months in comparison to basilixmab induction regimen
In long term even with alemtuzumab induction patients converted to sirolimus showed Increased risk of rejection and infections
How will the 3C study influence your practice?
I prefer to maintain the patient on tacrolimus, MMF and prednisolone and not to convert to sirolimus .
Summary:
Kidney transplantation remained the best renal replacement therapy for patients with ESKD that improved patient survival and better quality of life, short term graft and patients’ survival improved with the improvement of the IS therapy and better immunological screen and HLA matching however long-term graft survival still not optimal despite the use of potent maintenance IS including tacrolimus.Rapamycin inhibitors like sirolimus have been used in kidney transplantation since years ago and many studies reported higher rate of rejection, infection, on the other hand mTORi is associated with lower rate of malignancy post-transplantation (especially skin cancer).also, mTORi have more favorable effects on T regulatory cells expression and help in tolerance induction after alemtuzumab-based induction therapy, this effect found more after alemtuzumab-based induction therapy (1).
Aim and objectives of currnet study:
No previous randomized controlled trials have compared mTORi with CNIs in combination with either alemtuzumab- or basiliximab-based induction therapy ,So the current 3 c study designed to assess the possibility of using CNI free regimen as long-term maintenance therapy and determine its effect on the graft function by estimation of GFR at month18 of FU,cases of acute rejection and proteinuria of > 800mg were excluded from the study ,from the total of 852 patients and only 398 included at time of randomization, the two groups randomly allocated for tacrolimus based IS group and sirolimus based group regardless of the type of Induction IS, the data analysis based on intention to treat, both treating physicians and recipients were not blinded for treatment allocation, all P values are 2-sided.for BPAR used RR instead of hazard ratio which again can increase the underestimation in the results, in fact in the sirolimus group there were significant drop of 49% of the cases, compared to 6% in tacrolimus group, which explained by more noncompliance in sirolimus group 76% vs 99% in tacrolimus group at 3 months of FU and by 18 months after transplantation further drop to 91 (48%) and 180 (94%), respectively ,the poor compliance in sirolimus arm in this study reduces the sensitivity of the trial to detect a true difference in transplant function, also, the possible underestimation of the BPAR by using RR instead of hazard ratio, in addition the DSAs level monitoring missing in this trail as the presence of dnDSAswould impact the graft function.
More patients in sirolimus group develop AR and converted back to tacrolimus based IS at 6-month FU, so this add heterogenicity in data analysis and failed to achieve teh objective of this study , More infection and proteinuria in sirolimus group.
Conclusion:
The first 3C study designed to compare the immediate effects (acute rejection rate at 6 months) of the two-induction monoclonal AB, alemtuzumab vs basiliximab inductions and,had showed a highly significant halving of rejection in patients treated with alemtuzumab at 6 months (short outcome).the current c3 study conclude that the elective conversion to sirolimus at about 6 months after kidney transplantation regardless of the induction type does not improve subsequent transplant function at 18 months FU and carries significant risks of rejection and infection, also this study failed to show benefit with sirolimus on cancer rate, may be too early to assess such outcome, need longer FU, in fact most of the patinets in sirolimus arm converted back to tacrolimus maintenance IS .
I have no experience in use of alemtuzumab not available in our center
This study evaluate the long term graft function ( at 18 months after transplantation) in patients receiving sirolimus at 6 months vs. patients continuing on tacrolimus.
There was no statically significant difference in GFR in 18 months between the two groups.
The rate of acute rejection was higher in the sirolimus treated patients .
Serious infections was higher in the sirolimus treated group.
Sirolimus treated patients had higher risk of antibody mediated rejection.
No difference on cancer incidence is observed at 18 months.
Hyperlipidemia risk is increased with the use of sirolimus with increased cardiovascular events.
The strength of the study is that it includes patients with multiple centers .
The weakness of the study is that the study is open labelled , and non adherence level was high, and the DSA is not measured routinely.
In our center, we did not convert patients to mTOR routinely, but we convert them to mTOR when needed for clinical reasons eg. in patients who develop cancer.
Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial
In various studies, mTORi was tested to replace CNI, 6 months, posttransplantation and has been shown to improve function. Its de novo use (from the time of transplantation) was associated with complications and improvement in function. while an early conversion within 6 months, posttransplantation has been shown to improve function compared with cyclosporine based therapy.
mTORi is associated with reduced risk of malignancy especially skin cancer posttransplantation, although a recent meta-analysis reveals that sirolimus may be associated with increased mortality. mTORi have a good effect on tolerogenic T reg cells, especially after alemtuzumab induction.
This study aimed to test the hypothesis that alemtuzumab induction enables patients to become established on sirolimus maintenance therapy without problems. Test Sirolimus-versus tacrolimus-based therapy with induction with either alemtuzumab or basiliximab.
The study found that elective conversion to sirolimus at about 6 months posttransplantation carries significant risks of rejection (BPAR) and infection and does not improve function, even if the patient received alemtuzumab induction.
Infections, mainly the non-opportunistic (respiratory and gastrointestinal) were common in the sirolimus group. Other studies suggested that sirolimus may have an effect on viral replication and so, reduce the incidence of CMV.
In 3C study, infection is low, so they cannot make a strong conclusion.
Regarding cancer incidence, 3c study did not observe any effect of the sirolimus on it. This may be contributed to short follow up time as malignancies take several years to develop. In addition, this study is too small to make a reasonable effect on cancer risk.
The study, observe the sirolimus induced proteinuria effect also. And proteinuria is a risk factor for graft failure. During 3c study only a small number develop failure, so they cannot conclude the effect on graft survival. Post-transplant diabetes mellitus was increased in the sirolimus group as well, the non-high-density lipoprotein cholesterol although were non-significant.
The cardiovascular effect of sirolimus was adverse, but because of the small number of cardiovascular events, the study power was negligible.
Strength
It contained a wide range of various types of participants.
Weakness:
Only about half of the recipients enrolled at the time of transplantation entered the comparison
Non-adherence
They don’t monitor the DSA
3C study was the need for it to be open-label.
Only 18 months period of followup
CNIs improve short term graft survival but are associated with late graft fibrosis, nephrotoxicity and higher risk of late transplant failure.
This randomized controlled trial compares sirolimus versus tacrolimus based maintenance therapy.
The study showed that:
conversion of tacrolimus to sirolimus was associated with significant risk of rejection and infection.
There was no evidence that alemtuzumab induction therapy improved late graft function with sirolimus based maintenance
conclusion: the elective conversion of tacrolimus to sirolimus was not associated with improved graft function at 18 months post transplant regardless the induction therapy.
Strengths:
randomized participants with the analysis done according to intention to treat principal that reduce bias
Weaknesses:
*Only half of participants in the short term study were randomly assigned.
*Reasons for stopping sirolimus were collected during first 6 months only.
*By 18 months only 48% of participants assigned to sirolimus based therapy were adherent to treatment leading to decrease sensitivity of the study.
Inhibitors of the mammalian target of rapamycin pathway (mTORi, eg, sirolimus) were first tested in various strategies to replace CNI; however, de novo use (ie, from the time of transplantation) is associated with complications.
Late conversion from CNI-based therapy to mTORi found no improvement in subsequent function.
Where’s early conversion conversion to mTORi has been shown to improve transplant function .
conversion to mTORi is associated with a reduction in the risk of malignancy posttransplantation (especially skin cancer).
The first planned analysis of the 3C study, comparing the immediate effects of the 2 induction treatments, has been reported previously and showed a highly significant halving of rejection in patients treated with alemtuzumab.In the current report, the results of the sirolimus- versus tacrolimus-based maintenance therapy randomization are presented.
of the 852 participants who were randomly assigned to either alemtuzumab or basiliximab induction therapy,
820 were transplanted
394 were randomly assigned to sirolimus -based therapy versus tacrolimus -based therapy.
By 18 months after transplantation,91 of participants assigned sirolimus remained adherent compared to 180 of those assigned to tacrolimus -based therapy.
The most common reason for stopping sirolimus were rejection and infection
No effect on 18 months eGFR by both sirolimus and tacrolimus based therapy.
And no effect of induction type on the 18 months
eGFR
The 18 months eGFR amongst those who discontinue treatment were lower in the sirolimus-based compared to tacrolimus-based therapy.
After 18 months after transplantation sirolimus based therapy had less BPAR then tacrolimus based therapy (1 versus 6)
This risk was similar in alemtuzumab and basiliximab induction therapy.
Participants assigned sirolimus-based therapy experienced serious infections more than tacrolimus-based therapy.
No effect on cancer between the 2 groups
No effect on mortality between the 2 groups
No effect on the composite outcome of death or transplant failure.
No effect on NODAT
Anemia were more in sirolimus based therapy
Proteinuria more in sirolimus-based therapy
High cholesterol and triglycerides concentrations at 6 months among participants assigned sirolimus-based therapy.
Limitations:
under half of all participants recruited at the time of transplantation entered this com- parison.
Information on concomitant immunosuppression and reasons for stopping were collected for only 6 months after randomization.
the requirement for it to be open label.
Strength :
the 3C Study has established linkage with appropriate national registries, so longer-term follow-up will be conducted in a cost-effective manner and may yield informative results.
Deferenc between the 2 3 C study was :
Short term study shows less occurrence of BPAR , PTLD , and the rate of death in alemtuzumab based induction compared to basiliximab based
BK infection more in the alemtuzumab based group
Long term study no effect of the induction type on 18 months eGFR between sirolimus based maintenance compared to tacrolimus based therapy.
Anemia , cholesterol and proteinuria more in sirolimus
Less BPAR in sirolimus based group
More serious infection in sirolimus based group
No effect on mortality between sirolimus and tacrolimus groups.
In your own words, summarise this article.
Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short-term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long-term CNI renal damage and improve outcomes.
mTORi have more favorable effects than CNIs on tolerogenic T regulatory cells, and this effect may be most notable after alemtuzumab-based induction therapy.
A series of kidney transplant recipients treated with alemtuzumab, and elective conversion to sirolimus 6 months later reported good results, and it was hypothesized that the combination with alemtuzumab induction treatment enabled patients to become established on maintenance sirolimus without the problems that had limited previous studies (including increased rejection).
No previous randomized controlled trials have compared mTORi with CNIs in combination with either alemtuzumab- or basiliximab-based induction therapy.
The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation.
The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy .
Participants with a functioning transplant between 5 and 7 months after transplantation were eligible to participate in this comparison of tacrolimus- versus sirolimus-based maintenance therapy with 2 exclusion criteria: (i) a proven rejection episode in the previous month and (ii) proteinuria in excess of 800 mg daily (estimated by spot urine protein:creatinine ratio) .
852 participants entered 3C Study, 426 allocated to basiliximab based induction therapy and 426 allocated to alemtuzumab based induction therapy . 458 of them did not enter maintenance therapy comparison . 394 randomly allocated to maintenance treatment .197 allocated to sirolimus-based maintenance therapy and 197 allocated to tacrolimus-based maintenance therapy . 97 (49%) discontinued sirolimus-based maintenance therapy and 11 (6%) discontinued tacrolimus-based maintenance therapy . Exploratory analyses showed that ;
Sirolimus had no significant effect on eGFR at 18 months .
Biopsy-proven acute rejection and serious infections (defined as opportunistic infections or those requiring hospitalization were more
common among participants allocated sirolimus.
Compared with tacrolimus-based therapy, sirolimus-based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection.
What are the weakness and strength of this study?
strength of this study;
It was a large study, included a broad range of different types of participant .
The baseline characteristics of these participants were similar to those of the overall trial cohort, suggesting that this result is likely to be generalizable .
weakness of this study;
It was that just under half of all participants recruited at the time of transplantation entered this comparison .
Information on concomitant immune suppression and reasons for stopping were collected for only6 months after randomization.
The requirement for it to be open label.
The primary outcome (eGFR at 18 months after randomization) was collected by linkage with the UK Renal Registry, which, in turn, collects its data through routine extraction from hospital databases, making it highly unlikely that the values entered would be biased with respect to treatment allocation.
Compare conclusion of the short-term with long-term study.
Alemtuzumab –based induction therapy in short term is associated with reduced acute rejection rate when a low dose CNI is used as a maintenance therapy .
Alemtuzumab –based induction therapy in long term is associated with increased risk of acute rejection rate when MTOR inhibitor is used as maintenance therapy .
How will the 3C study influence your practice?
Alemtuzumab is not available and we do not use it .
Strength of the study
This study is a randomized controlled clinical trial with a level 1 of evidence.
A broad range of different types of participants and recruited about one-eighth of all kidney transplant recipients transplanted in the participating centers during the recruitment period. Therefore, results are likely to be relevant to a broad population of patients.
Weakness of the study
Low adherence to sirolimus-based therapy (about 50%) reduces the sensitivity of the trial to detect a true difference in transplant function, and it means that estimates of the hazards may be less than would be observed with full adherence.
Another limitation was the requirement for it to be an open label.
DSAs didn’t measure in this trial.
Chronic nephrotoxicity of CNIs may contribute to late transplant loss. Elective conversion to mTOR inhibitors has been proposed to reduce long-term CNIs nephrotoxicity.
De novo use of mTOR inhibitors was associated with some complications. Although late conversion (>6 months) to mTOR inhibitors from CNI-based therapy found no improvement in kidney function, early conversion (< 6 months) has been shown in some trials to improve kidney function.
Another benefit of mTOR inhibitors is lower risk of malignancy. They also have more favorable effects on Treg cells, especially after alemtuzumab based induction therapy.
This study compares outcomes between tacrolimus-based and sirolimus-based maintenance therapy in combination with either Alemtuzumab-based or Basiliximab-based induction therapy during 18 months post transplantation.
In comparison of Tacrolimus-based to sirolimus-base maintenance immunosuppression therapy:
· By 18 months, higher adherence to therapy in tacrolimus-based group (94% vs 48%), most common due to rejection or infection in sirolimus-based group.
· No difference in mean eGFR between patients in two groups who have continued their therapies.
· Lower incidence of episodes of acute rejection in tacrolimus-based group (3% vs 14.7%). These results were similar in different induction therapy.
· Among patients who experienced rejection in the sirolimus group, mean eGFR was 7.1ml/min lower than in the tacrolimus group.
· More patients in sirolimus-based therapy experienced serious infection. (48.2% vs 35.5%), especially excess of non-opportunistic infections was reported.
· There was no significant difference in transplant failure, incidence of cancer, mortality, NODAT, and major vascular events.
· The incidence of anemia, proteinuria and higher cholesterol and triglyceride concentrations was higher in the sirolimus-based therapy group.
· Sirolimus-based maintenance therapy was not more effective after alemtuzumab-based than basiliximab-based induction therapy.
In conclusion, this study’s findings suggest that elective conversion to mTOR inhibitors at about 6 months after kidney transplantation does not improve kidney function and is associated with significant risks of rejection and infection even in the context of benefits of Alemtuzumab induction therapy.
In short term study, Alemtuzumab induction therapy is associated with lower risk of acute rejection without an excess of serious complications, and in long-term study, conversion to mTOR inhibitors is not suggested even in the context of alemtuzumab induction therapy because of significant risks of rejection and infection.
CNI is the main immunosuppression drug in maintenance therapy but it was found to lead to long term transplant failure, therefore m TOR inhibitors were tested to replace it .
Trials concluded that early shifting from CNI to m TOR inhibitors as sirolimus is accompanied with better out come in comparison to late shifting which also reduces the risk of post trasnplanation malignancy and has a tolerogenic effect particularly if given with alemtuzumab induction therapy
The 3 C study addresses the outcome of combining mTOR inhibitors and CNI after either alemtuzumab or basiliximab induction therapy to access the possibility of keeping patients on long-term CNI-free immunosuppression and it’s effect in reducing graft failure
Patients were randomized equally to either sirolimus based maintenance therapy or tacrolimus-based maintenance therapy and followed at 3 and 6 months.
The study demonstrated that conversion to sirolimus at 6 months post transplantation didnot improve graft function and increased the risk of rejection and infection regardless of induction therpy
In contrast to previous studies no evidence that sirolimus-based maintenance therapy was more effective after alemtuzumab-based than basiliximab-based induction therapy.
3C trial noticed that sirolimus-based maintenance therapy increased the risk of BPAR and the risk of infection specially non opportunistic as well as protienuria
Sirolimus based therapy effect on cancer incidence was not observed in this study due to the short period of the study as post transplantation malignancies take years to occur.
–The strength is including a large number of different types of participants nearly one-eighth of all kidney transplant recipients transplanted in the involved centers during this specific period of time
Collecting the data in conjugation with UK Renal Registry making the bias probability less
Also it used tacrolimus instead of cyclosporine which was applied in most of the previous studies as the former is the currently widely used CNI along with MMF which was not studied before
Tacrolimus is proved by multiple previous studies to be less nephrotoxic than cyclosporine.
The weak points of the 3C study is being an open label study also the lack of adherence of participants to sirolimus based therapy, another point is that DSA was not measured which is an important determinant of graft function.
– The 3C short term study suggested that alemtuzumab induction therapy followed by reduced CNI therapy ,low dose MMF and steroid avoidance lowered the acute rejection risk in the first 6 months post transplantation in comparison to usual basilixmab induction regimen with no increase in CMV infection risk
The 3C long term study suggested that elective conversion to sirolimus-based maintenance therapy did not improve transplant function 18 months later and is associated with rejection and infection.
-I think that alemtuzumab can be used in induction therapy followed by low dose CNI ,MMF in the suitable group of patients and Sirolimus can be preserved to certain group of patients as those with malignancy history or post transplantation malignancy because the treatment has to be tailored according to each case on individual bases.
The 3C Study is a RCT,in it’s short term( first 6 months) studying and assessing the efficacy and safety of alemtuzumab compared with basiliximab treatment as induction therapy in patients receiving kidney transplants. The 3C study in it’s long term(after 6 ) assessing the efficacy of TAC in comparison to Sirolimus in maintenance therapy.
The primary outcome of long term 3C study is to assess the eGFR at 18 months after maintenance therapy with CNI in comparison to mTOR inhibitor .
Despite of potential benefits of mTORi in lowering the rate of post-transplantation malignancy, they are associated with adverse events in early transplant period at time of surgery. One of great favor of mTORi over CNIs is it’s positive impact on tolerance induction via Treg.
Study Results :
Strength of the study:
Its multicenter RCT
Weakness of the study:
– Open-label trial.
– Less than 50% of original study population underwent randomization at 6 months post-transplant
– Low adherence in sirolimus group
Compare conclusion of the short-term with long-term study.
In short-term, alemtuzumab induction helped in reducing CNI dose and avoiding steroids and was still associated with reduced acute rejection episodes in first 6 months post-transplant. But in long term, patients, if converted to sirolimus maintenance immunosuppression it associated with high risk of rejection .
How will the 3C study influence your practice?
Iprefer Alemtuzumab as induction therapy followed with low dose TAC,MMF and Prednisolone as maintenance therapy. Although isn’t’ available in our country
Summary:
CNIs improve short term graft survival but are associated with late graft fibrosis and higher risk of late transplant failure.
Several trails aimed to decrease CNI exposure through starting mTORi from time of transplant but this was associated with several complications, others tried late conversion from CNI to mTORi but didn’t show improvement in graft survival.
This randomized controlled trial compares sirolimus (started 5-7 months post transplant) versus tacrolimus based maintenance therapy.
The study showed that
elective conversion of tacrolimus to sirolimus 6 months post transplant was associated with significant risk of rejection and infection with higher rate of non-opportunistic infection
There was no evidence that alemtuzumab induction therapy improve late graft function with sirolimus based maintenance
conclusion: the elective conversion of tacrolimus to sirolimus was not associated with improved graft function at 18 months post transplant regardless the induction therapy.
Strength:
large study
randomized participants with the analysis done according to intention to treat principal that reduce bias
Weakness:
open label trial
only half of participants in the short term study were randomly assigned.
by 18 months only 48% of participants assigned to sirolimus based therapy were adherent to treatment leading to decrease sensitivity of the study.
reasons for stopping sirolimus were collected during first 6 months only
analysis was based on only 18 months follow up.
This is a sequential study to the clinical trial of alemtuzumab and basiliximab, in which a comparison between tacrolimus and sirolimus was done. The study included out of the 820 patients who were in short arm, 397 patients. There were 197 patients in each group. They were followed for 18 months. The adherence was more with tacrolimus at 3 months after maintenance therapy randomization and after 18 months. There was a chance for those on sirolimus to shift for tacrolimus . Most patients stopped using sirolimus within the first 6 months due rejection and infection. There was no difference between both groups regarding eGFR at 18 months. On the other hand, the sirolimus group has more biopsy-proven acute rejection. At 6 months, sirolimus group have anemia, proteinuria, higher cholesterol and higher triglyceride .
Weakness
· under half of all participants of the short arm were actually entered this comparison.
· Information on medication taken were collected for only 6 months
· Open label study
· The study did not count the effect of DSA as a confounding factor
Strength
· The baseline characteristics of all participants were comparable
· the primary outcome (eGFR at 18 months) was not biased as it was collected through authorized Registry and this will give a chance to have longer term follow up
How will the 3C study influence your practice?
I think this study contradict the known fact that sirolimus is associated with less infection. We face many patients with Kaposi sarcoma, CMV &BK for whom we convert the tac to sirolimus (for the last two we try to reduce the IS first).
Compare conclusion of the short-term with long-term study.
18 months e GFR was comparable between regardless of the induction type of drug. The 3C study rejected the “prope” (near) tolerance hypotheses stating that sirolimus-based maintenance therapy was more effective after lymphocyte-depleting agent than nondepleting. The 3C proved using lymphocyte-depleting agent will not facilitate the conversion to sirolimus at 6 months.
1. In your own words, summarise this article.
Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial
Kidney transplant is the treatment of choice for end stage renal disease. Use of calcineurin inhibitors (CNI) is associated with poor long-term graft function. Early convertion of CNI to mTOR inhibitors have been shown to be associated with improved graft function. Based on these observations, patients in this prospective, open-label, multi-center trial (who initially received either alemtuzumab or basiliximab as induction therapy, and were on tacrolimus and MMF maintenance immunosuppression, and steroids if given basiliximab) were randomized 6 months post-transplant into either continuing with tacrolimus based maintenance immunosuppression, or converting to sirolimus based maintenance immunosupression.
A total of 394 patients out of 852 patients were randomized into 2 arms (tacrolimus and sirolimus arm). They were followed upto 18 months post-randomization, eGFR was calculated using MDRD equation.
Adherence in sirolimus group reduced to 48% at 18 months, while it was 94% in the tacrolimus group. There was no effect of induction therapy on eGFR at 18 months in either group.
The sirolimus group was associated with significantly increased risk of biopsy proven acute rejection (14.7% versus 3%). It was also associated with increased risk of any serious infection as well as non-opportunistic infections, including respiratory and gastrointestinal infections. There was a significantly increased association of anemia, proteinuria, elevated serum cholesterol and triglycerides in the sirolimus group. A non-significant increase in non HDL levels and post transplant diabetes mellitus (PTDM) was observed in sirolimus group. There was no significant difference with respect to transplant failure, malignancy or mortality.
Hence the study concluded that conversion of CNI to mTOR inhibitors post-transplant is associated with poor adherence, does not improve graft function and is associated with increased risk of rejection and serious infections.
2. What are the weakness and strength of this study?
Weaknesses:
1) Open-label trial.
2) Less than 50% of original study population underwent randomization at 6 months post-transplant
3) Low adherence in sirolimus group: associated with decreased sensitivity to detect a true difference in the graft function.
4) Estimate of hazard low due to poor adherence
5) DSA not measured in the trial, hence an important factor in long-term graft function has not been analyzed.
6) The follow-up period is relatively small to comment on effect on malignancy risk
7) The trial is too small to comment on risk of malignancy, graft failure and death due to cardiovascular events.
Strengths:
1) Multi-center, prospective, randomized trial
2) Although the patients randomized for the maintenance phase were only 50% of the initial study population, the baseline characteristics remained similar, hence the results would not have been changed much.
3. Compare conclusion of the short-term with long-term study.
In short-term, alemtuzumab induction helped in reducing CNI dose and avoiding steroids and was still associated with reduced acute rejection episodes in first 6 months post-transplant. But in long term, patients, if converted to sirolimus maintenance immunosuppression (even with alemtuzumab induction), suffer increased episodes of acute rejection as well as serious infections.
4. How will the 3C study influence your practice?
Although we do not have alemtuzumab available for use, it could be utilized in patients as an induction agent with low dose tacrolimus and MMF as maintenance immunosuppression. c]Changing over to mTOR inhibitors would not be useful, hence patient should remain on tacrolimus based regimen.
summarise this article:
The hypotheses for the 3C Study revealed that using lymphocyte-depleting induction treatment would help the conversion from tacrolimus to sirolimus at 6 months.
The use of sirolimus maintenance treatment following alemtuzumab induction therapy was no more successful than nondepleting basiliximab induction therapy.
Alemtuzumab may produce (near) tolerance when used with sirolimus. Despite the positive pilot study results, we observed no impact on transplant function, which matches small studies utilizing histologic outcomes.
Our discovery that sirolimus-based maintenance medication increased the likelihood of BPAR. We found minimal evidence that people who stayed on sirolimus benefited more from the tacrolimus group.
In addition, infections were more likely in patients receiving sirolimus-based treatment.
However, previous research has shown that sirolimus may interfere with viral replication and, as a result, lower the frequency of CMV infections. This study did not find any evidence of this.
Among patients who received sirolimus-based medication, a greater proportion of nonopportunistic infections (particularly respiratory and gastrointestinal infections) was seen, which explained the increase in overall severe infections.
We did not observe any effect on cancer incidence. Sirolimus
has been shown to inhibit the development of nonmelanoma skin
cancer and other cancers. But the short term of the study may be the cause of not discovering the effect on cancer.
We observed the known effects of sirolimus on proteinuria. Also, The increase in non–high-density lipoprotein cholesterol.
In our study, we discovered that, when compared to continuing with a tacrolimus-based regimen, elective conversion to sirolimus-based maintenance therapy did not improve transplant function 18 months after the procedure (regardless of induction therapy) and was associated with significant risks of rejection and infection.
weakness:
-In this trial, there was poor adherence to sirolimus.
-short term follow-up, so the effect of sirolimus on malignancy was not clear.
-under half of all participants recruited at the time of transplantation entered this comparison.
-Strength:
a large number of volunteers from a variety of transplantation facilities were shared in the study.
– the baseline characteristics of these participants were similar to those of the overall trial cohort.
–The findings of a short-term study: suggest that alemtuzumab-based induction treatment followed by CNI reduction and low-dose mycophenolate and steroid avoidance can significantly reduce the risk of acute rejection in the first 6 months after transplantation.
–the long term study: suggest that elective conversion to sirolimus-based maintenance medication did not enhance transplant function 18 months after the surgery (independent of induction therapy) and increased risks of rejection and infection.
Reflection on my practice:
After reviewing this study, I think the role of sirolimus in the clinical practice in transplantation is very limited.
but in our centre, We still use sirolimus in Skin Cancer(especially Kaposi sarcoma’) with an acceptable result.
Dear all
1. What is the difference between this 3C study and the previous 3C study?
Patients in 3C study (2014) received either alemtuzumab or basiliximab as induction therapy, and were on tacrolimus and MMF maintenance immunosuppression, and steroids if given basiliximab). 852 patients of 3C study (2014) became the pool from which patients were enroled for 3C study (2017) in which 394 patients were randomized 6 months post-transplant into either continuing with tacrolimus based maintenance immunosuppression, or converting to sirolimus based maintenance immunosupression.
They were followed upto 18 months post-randomization.
So the 3C (2014) study gave insights into short-term effects of alemtuzumab while 3C (2017) focused more on effects of sirolimus on graft.
2. In your words, mention two critical limitations of this study protocol?
2 critical limitations in this study include
1) Less than 50% of original study population underwent randomization at 6 months post-transplant
2) Low adherence in sirolimus group: associated with decreased sensitivity to detect a true difference in the graft function.
In my opinion, it would have interesting to see the long-term effect on the 2 original groups rather than creating a complex situation with multiple permutations and combinations, especially with decreased adherence in the sirolimus group.
Summary of the Article
The 3C Study is a RCT,in it’s short term( first 6 months) studying and assessing the efficacy and safety of alemtuzumab compared with basiliximab treatment as induction therapy in patients receiving kidney transplants. The 3C study in it’s long term(after 6 months post-transplantation) assessing the efficacy of TAC in comparison to Sirolimus in maintenance therapy.
The primary outcome of long term 3C study is to assess the eGFR at 18 months after maintenance therapy with CNI(TAC) in comparison to mTOR inhibitor(Sirolimus). The long term nephrotoxic effects and adverse reactions of CNI potentiated the search and study looking for more effective and safe agents to minimize CNI toxicity, the 3C study is one of that studies.
Despite of potential benefits of mTORi in lowering the rate of post-transplantation malignancy, they are associated with adverse events in early transplant period at time of surgery. One of great favor of mTORi over CNIs is it’s positive impact on tolerance induction via Treg.
Study Results and Discusion:
What are the weakness and strength of this study?
Strength of the study:
Weakness of the study:
Compare conclusion of the short-term with long-term study.
The 3C; short term study findings suggest that alemtuzumab-based induction treatment followed by CNI reduction and low-dose mycophenolate and steroid avoidance can substantially reduce the risk of acute rejection in the first 6 months after transplantation, without causing an excess of serious or opportunistic infections or other known complications of immunosuppression.
The 3C; Long term study findings suggest that elective conversion to sirolimus-based maintenance therapy does not improve transplant function 18 months later (regardless of induction therapy) and is associated with significant hazards of rejection and infection.
How will the 3C study influence your practice?
From the 3C study I will prefer Alemtuzumab as induction therapy followed with low dose TAC,MMF and Prednisolone as maintenance therapy.
Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial
short graft survival improved in the era CNI but long term graft survival not improved
alemtuzumab induction followed by low dose CNI and steroid free regimen looks wise plan to decrease CNI nephrotoxicty and decrease steroid complications
the results showed the safety and efficacy of this regimen in 1st 6m post transplant n first 6 months post transplantation it was found the following:
after first 6 months the patients were allocated again into 2 group
low dose tacrolimus(CNI based) vs shifting tac to sirolimus (CNI free ) aiming to improve long term graft survival and patients were observed prospectively for 18months and results showed
1/campath induction didn’t afford good immunological cover for CNI free replacement with sirolimus and associated with increase risk of rejection
2/sirolimus based regimen showed no superiorty in cancer prevent and show the same incidence of maliganacy in comparison to tac
3/sirolimus showed no benefit in infection prevention specially CMV and showed rate of incidence in comparison to tac
4/sirolimus is associated with greater incidence of graft rejection and no significant difference in eGFR
5/SIROLIMUS associated with increase risk of proteinuria and hyperlipidemia with no increase in CVS death
strength of this study:
1/well allocation of patients and distribution on randomized base
2/involve wide variant of age, race, different immunological risk so it can be generalized
weakness
1/not blinded and this affected on patients compliance
2/funded by pharmaceutical companies which carry conflect of interest
3/mTOR in combination to small dose tac rather than replacement is not evaluated
my own reflection after 3c studies
although CNI affect long term graft survival by its nephrotoxicity but still the main corner stone in kidney transplantation and unreplaceble
CNI-based maintenance IS regime is very important in first 6 months post-transplantation in reducing AR rate, but on long-term it may cause graft fibrosis & atrophy leading to graft loss. Although mTOR-I associated with reducing risk of malignancy , it associated with increase all cause of mortality, and de novo mTOR-I based regime a transplantation complications. Early conversion ( first 6 month) of CNI to mTOR-I had conflict results about graft survival, but late conversion ( after 6 months post transplantation) is associated with improved graft out-come.
It was found that mTOR-I based maintenance regime with alemtuzumab as induction associated with enhancing tolerance through Treg cells.
This is randomized controlled study enrolled 852 patients from different transplant center. ALL patients included in this study were above 18 years of age who planned for transplantation in next 24 hours. The patients divided into 2 groups based on type of induction ( alemtuzumab vs basiliximab) with CNI-based maintenance IS & followed for 5-7 months. The eligible patients are divided again into 2 groups based on type maintenance IS ( CNI vs mTOR-I) with only 2 exclusion:
The study found the following:
Strength of the study: large number of participants from different transplant centers
Weakness of the study: open-labelled study, non adherence to sirolimus
Short term conclusion:
Long-term conclusion:
CNI has the advantage of reducing the incidence of rejection but on the other hand, increase the risk of CAN
From several previous trials, Conversion to sirolimus was associated with the following :
The outcome of conversion to sirolimus differ according to timing :
The use of Alemtuzumab as an induction agent together with switching to sirolimus was proposed by some studies to decrease CAN without an increase in the side effects of sirolimus
The current study found that use of alemtuzumab togetrher with late conversion to sirolimus was associated with the following :
Conclusion
Strength
Weakness
In my practice, we do not use alemtuzumab
This is a prospective study that evaluated the renal outcomes of 2 groups based on maintenance immunosuppressive therapy. Two group of patients were randomly assigned to either alemtuzumab-based induction treatment followed by steroid free regimen consisting of low-dose tacrolimus and mycophenolate or basiliximab-based induction treatment followed by standard-dose tacrolimus, mycophenolate, and prednisolone. The maintenance therapy at 6 months after transplantation was either sirolimus based maintenance therapy after immediate cessation of tacrolimus or tacrolimus-based maintenance therapy.
The primary outcome was eGFR at 18 months after maintenance therapy using MDRD equation.
Secondary outcomes included all acute rejection episodes and rate of infections and adverse events.
Results
Out of 820 transplanted, 394 were randomly assigned to sirolimus-based therapy versus tacrolimus-based therapy.
At 3 months of maintenance therapy after randomization, 24% of participants assigned sirolimus-based therapy were shifted back to tacrolimus, compared with 195 (99%) of those assigned tacrolimus-based therapy who continue same regimen.
At 18 months after transplantation, only 48% of participants in the sirolimus arm continued sirolimus, Compared to 94% in the tacrolimus group.
The most common reasons for stopping sirolimus, reported during the first 6 months after randomization were rejection and infection.
During the 18 months after randomization,14.7% of participants in the sirolimus-based therapy had at least 1 episode of BPAR compared with 3.0% in the tacrolimus-based therapy.
The mean eGFR among participants was almost the same at 53 ml/min at 18 months among 2 groups.
No difference in eGFR among participants who received alemtuzumab-based induction therapy vs participants who received basiliximab-based induction therapy.
serious infection requiring hospitalization or opportunistic infection were more common in the sirolimus-based therapy group.
Conclusion
Findings of this study suggest that conversion from Tacrolimus to sirolimus at about 6 months after kidney transplantation is associated with increase risk of rejection and adverse events.
Weaknesses of the study
Less than half of all participants recruited at the time of transplantation entered this comparison and only few patients remained in the Sirolimus group.
The study is not open label.
Strength of the study
The study compared 4 mixed induction and maintenance immunosuppressive drugs which can come out with many conclusions on the combination regimens.
3C Study has established linkage with appropriate national registries.
In my practice
Alemtuzumab is not available and we do not use it in practice.
CNI either cyclosporin or tacrolimus are usually associated with decrease short term graft failure or loss , but this will happen on long term follow up because of their nephrotoxicity especially cyclosporin, so conversion to mTor inhibitors like sirolimus is possible to improve graft survival and avoid CNI nephrotoxicity.
As regard induction, alemtuzumab is better than basiliximab as regard incidence of BPAR which is 50% less in the group with alemtuzumab.
As regard conventional therapy, the study compared CNI based protocol with CNI converted to sirolimus protocol as regard graft survival and outcome. Combination between induction with alemtuzumab with conventional CNI conversion to sirolimus compared to basiliximab induction with CNI based conventional therapy is studied.
Sirolimus conversion 6 months post transplant is associated with avoidance of CNI nephrotoxicity and will help in tolerance induction and this will be evident and has longer effect if combined with alemtuzumab induction which is also causing creation of the state of tolerance.
But the study showed that regardless the induction therapy either alemtuzumab or basiliximab, the conversion from CNI to sirolimus at 18 months post transplant will not add any benefit to graft survival but will increase rate of rejection.
in my practice we don not use alemtuzumab, and we shifted from CNI to sirolimus when there is nephrotoxicity from cyclosporin or neurotoxicity from tacrolimus.
The 3C study was a pragmatic randomized controlled trial of sequential randomization between Alemtuzumab and Basiliximab induction therapy and between Tac and sirolimus maintenance therapy at 6 months post transplant.
The study get approval from the national research ethics committee.
Inclusion criteria:
age > 18 years if they receive a kidney transplant within 24 hr.
participants with a functioning graft who received kidney graft 5-7 months ago were eligible to participate in comparison of Tac versus Sirolimus.
Exclusion criteria:
197 patients were on the Tac arm and 197 patients received Sirolimus.
participants were reviewed at 3 and 6 months after maintenance therapy.
Follow up for BP, blood and urine samples for creatinine, CBC, Tac and Sirolimus level, urine protein-creatinine ratio or albumin-creatinine ratio.
The primary outcome was eGFR at 18 months ( measured by MDRD equation).
Results:
Sirolimus has no significant effect on eGFR at 18 months, rejection and serious infections were more common in Sirolimus group,,, So compared to Tac therapy, Sirolimus based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with increased rejection risk.
There was no evidence that the effect on 18 month eGFR differed by induction therapy allocation.
Limitations of the study:
Strength of the study:
The 3C study established linkage with other national registries, so long term follow up will be cost effective and will yield informative results.
In my practice, we do not have Campath. most of our patients are on Tac maintenance therapy, very few patients are on sirolimus.
In your own words, summarise this article.
Short term transplant survival has improved in the short term but long-term rates have not improved in recent decades. CNI are associated with graft fibrosis, atrophy, worsening transplant function and long term transplant failure. minimising CNI exposure may reduce the rate of late transplant failure. mTORi have more favorable effects than CNIs on tolerogenic T regulatory cells, and this effect may be most notable after alemtuzumab-based induction therapy.
3C study
Inclusion criteria- 18 years or older were eligible to participate if scheduled to receive a kidney transplant within 24 hours.
Induction therapy – randomly allocated (either alemtuzumab or basiliximab based)
Maintenance therapy- all participants received tacrolimus and mycophenolate (and prednisolone if assigned basiliximab).
Participants with a functioning transplant between 5 and 7 months after transplantation were randomized equally to either
(i) sirolimus based maintenance therapy (immediate cessation of tacrolimus and sirolimus started on next day: 3 mg daily [or 2 mg if weight <50 kg]; target trough concentration 6-12 ng/mL for the first 6 months, thereafter 5-10 ng/mL) or
(ii) tacrolimus-based maintenance therapy (target trough concentration 5-7 ng/mL).
All participants also received mycophenolate and prednisolone.
2 exclusion criteria:
(i) a proven rejection episode in the previous month and
(ii) (ii) proteinuria in excess of 800 mg daily (estimated by spot urine protein:creatinine ratio
Participants were to be reviewed at 3 and 6 months after maintenance therapy randomization. At each follow-up visit,
blood pressure
weight were to be measured
blood and urine samples were collected for local analysis of creatinine, full blood count, tacrolimus and sirolimus concentrations
urine protein:creatinine ratio
The primary outcome of estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization was calculated by MDRD formula.
Findings –
Elective conversion to sirolimus at about 6 months after kidney transplantation does not improve subsequent transplant function and carries significant risks of rejection and infection.
What are the weakness and strength of this study?
Strength –
Study included a broad range of different types of participant and recruited about one-eighth of all kidney transplant recipients transplanted in the participating centers during the recruitment period.
Largest such trial.
Trial was done with tacrolimus versus sirolimus.
Weakness –
adherence to sirolimus-based therapy was low in the 3C Study.
DSA was not measured.
Compare conclusion of the short-term with long-term study.
Short term – highly significant halving of rejection in patients treated with alemtuzumab.
Long term- compared with continuation of a tacrolimus-based regimen, elective conversion to sirolimus-based maintenance therapy does not improve transplant function 18 months later (regardless of induction therapy) and is associated with significant hazards of rejection and infection.
How will the 3C study influence your practice?
Will use tacrolimus, MMF and prednisolone as maintenance.