IV. Calcineurin Inhibitor-Sparing Strategies in Renal Transplantation: Where Are We? A Comprehensive Review of the Current Evidence
- Please summarise this article.
- What are the different approaches calcineurin inhibitor-sparing immunosuppression?
- Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
- Give examples of calcineurin inhibitor-minimization protocols.
summary:
CNI introduction was associated with lower incidence of graft rejection but CNI toxicity may decrease graft survival so CNI sparing regimen with motor ,MMF and belatacept are emerging currently .
Acute CNI nephrotoxicity manifested as hypertension, tremor, seizure, TMA & renal dysfunction. Chronic CNI nephrotoxicity characterized histologically by striped interstitial fibrosis, tubular atrophy, medial arteriolar hylinosis & tubular micro calcification.
CNI sparing protocols:
1-CNI- avoidance:
– using T cell depleting agents or IL2-R blockers with maintenance (MFF, steroids).ass with high incidence of rejection in early 6 months of transplantation
-use of de novo :growth trial :it was ass with high rejection rates compared to CSA ,flechner >less incidence of CAN,ELITE SYMPHONY >high rate of ABMR and less survival than tacrolimus
Using belatacept :showed better survival and less rejection rate
2- CNI withdrawal:tapering till elimination kasiske. Study CSA withdrawal was ass with increased risk of ABMR but no significant effect on graft survival
3-CNI conversion:
CONVERT study show that change CNI to mTOR-I 6-12 months post transplantation in recipients with GFR >40 not associated with no effect on eGFR, acute rejection or mortality, but there was significant increase in proteinuria. So change CNI to mTOR-I should be early before significant parenchymal injury( reduced GFR, proteinuria).
conversion early after transplantation: several trials study the effect of CNI conversion mTOR-I in 10-24days, 1-3 months & after 3 months post transplantation , it show an improvement in eGFR without significant increase in ABMR.
conversion og CNI to sirolimus due to non renal adverse effects: as in recipients with SCC, the using of sirolimus was associated with reduced recurrence of SCC.
Most trials of CNI sparing regime had short-term follow-up & DSA monitoring was not done.
CNI minimization: mean using of low dose CNI de novo or reduce the CNI dose due to side effects. CAESAR and ELITE SYMPHONY
CNI still corner stone of immunosuppression .main maintenance protocol is low dose Tac, MMF & steroids ,avoid mTOR-I de novo use, patients can benefit from conversion from CNI to mTOR-I in low immunological risk & GFR >40 without significant proteinuria.
using of belatacept in recipients with CNI nephrotoxicity, persistent ATN, TMA in addition to inability to conversion to mTOR-I or can’t undertake CNI elimination.
-CNI- cyclosporine, and tacrolimus in the immunosuppressive regimens for a kidney transplant have been associated with reductions in the incidence of acute
rejection, with a subsequent improvement in 1-year graft survival but no improvements in long-term allograft survival. CNIs have a lot of toxicities.
Calcineurin inhibitor-sparing strategies:
1. Calcineurin inhibitor avoidance:
-Antibody induction( daclizumab) ,mycophenolate mofetil, and steroids.
-Use of sirolimus
–Use of belatacept.
2. Calcineurin inhibitor minimization:
-CNI minimization with mycophenolic mofetil.
-CNI minimization with mTOR
-CNI minimization with alemtuzumab
3. Calcineurin inhibitor withdrawal:
-CNI withdrawal from azathioprine and steroid regimen
-CNI withdrawal from mycophenolate mofetil and steroid regimen in patients with or without renal dysfunction
-CNI withdrawal from sirolimus based regimen
4. Calcineurin inhibitor conversion:
-Conversion late after transplant
-Conversion early after transplant
-CNI conversion to sirolimus due to adverse effects other than nephrotoxicity
-Calcineurin inhibitor minimization is better than CNI avoidance to decrease the risk of rejections and graft loss.
Summary of the article
Using CNI as immunosuppression regimens in kidney transplant recipients allowed reductions in the incidence of acute rejection,and improvement in 1-year graft survival unfortunately it was also associated with reduced graft survival in long-term due to toxicity .
CNI sparing protocols aimed to to reduce these side effects for a better graft outcome on long term.
chronic immune injury mediated by donor-specific antibodies may account for most late graft losses. Although some patients do benefit from calcineurin inhibitor-sparing protocols, others may have late allograft loss from chronic and subacute immune-mediated injury.
Most of calcineurin inhibitor-sparing studies have short-term follow-up and have not explored the change in the donor-specific antibody profile.
Histological changes of Chronic nephrotoxicity shows striped interstitial fibrosis, tubular atrophy, medial arteriolar hyalinosis, and tubular microcalcification.
Calcineurin inhibitor-sparing strategies:
1-Antibody induction, mycophenolate mofetil, and steroids Using daclizumab as an induction agent did not use an alternative
immunosuppressant , and this was ineffective 6-month acute rejection rate of 48%.
2-Use of de novo sirolimus
ELITE-SYMPHONY study concluded that tacrolimus was associated with better GFR at 1 year ,lowest rate of biopsy-proven acute rejection (BPAR) and the best allograft survival.
The sirolimus arm had the highest BPAR and the lowest allograft survival, more adverse events and a greater rate of treatment failure.
sirolimus with low dose tacrolimus have better result than complete avoidance of CNI.
3-Calcineurin inhibitor avoidance with belatacept;
chronic allograft nephropathy was similar in patients received CNI and balatacept.
belatacept was associated with a significant improvement in renal function using calculated GFR versus the CNI group 1 year post transplant.
Belatacept was associated with improvement in renal function at 7 years with but there was a higher incidence of PTLD .
In balatacept group there was more episodes of BPAR than cyclosporine group at 5 years .
Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
CNI minimization is more feasible to gain the benefits of decrease the long term nephrotoxic effect of CNI and decrease risks of acute and chronic rejection.
Calcineurin inhibitor minimization protocols;
1 low dose CNI with steroids and MMF, using Daclizumab induction .
2 CNI- minimization with mTORi immunosuppression:
3 CNI-minimization with alemtuzumab induction.
1/Summary of the Article:
The use of CNI in renal transplantation is associated with significant reduction in rate of rejection and further improvement in graft survival. Chronic nephrotoxicity associated with the use of CNIs potentiated many researchers to look for minimization of such adverse event by CNI-sparing strategies.
CNIs cross passively the cell membrane to bind immunophilins(CsA binds to cyclophilin and TAC binds to FK506-binding protein) to inhibit T-cell activation via inhibition of nuclear factor of activated T-cell dephosphorylation.
cause .
2/What are the different approaches calcineurin inhibitor-sparing immunosuppression?
1.Antibody induction using Daclizumab , mycophenolate mofetil, and steroids.
2.Use of de novo sirolimus plus Basiliximab as induction therapy.
3.The ELITE-SYMPHONY study including CNI-free arm: daclizumab induction, MMF, and steroids in combination with low-dose cyclosporine, low-dose tacrolimus, and low-dose sirolimus.
4.CNI-avoidance with newer drugs (belatacept).
3/Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
CNI minimization is more feasible than sparing strategies as CNIs have a great role in reducing episodes of AR and graft loss in the first post transplant period.
4/Give examples of calcineurin inhibitor-minimization protocols.
(CNI-minimization Strategies
1.low dose CsA plus MMF,CS and Daclizumab induction when CsA withdrawal is attempted
2.CNI minimization with mycophenolic mofetil ;
3.CNI- minimization with mTORi immunosuppression:
4.CNI-minimization with alemtuzumab
1. Please summarise this article. The introduction of the CNI in the immuno suppressive regimens for kidney transplant has been associated with marked reductions in the incidence of acute rejection, with a subsequent improvement in 1-year graft survival. But it reduce the graft survival in long-term because of toxicity . CNI sparing strategies have been employed to overcome these effects for a better graft outcome
2. What are the different approaches calcineurin inhibitor-sparing immunosuppression?A .CNI avoidance;
1- Using induction with daclizumab or antithymocyte globulin with complete avoidance of CNI was associated with high acute rejection rate
2- Using mTOR with antimetabolite and steroid (ELITE-SYMPHONY study). sirolimus with low dose tacrolimus have better result than complete avoidance of CNI
3- CNI avoidance with belatacept is comparable to cyclosporine but with more AMR later on . Switching from CNI-based regimen to a belatacept-based regimen after more than 6 months but less than 36 months after transplant
B.CNI minimization
1- with mycophenolic mofetil . There was no difference after 2 year between fixed-dose and the concentration controlled MMF .
2- with mTOR inhibitor showed no differences in renal function, rejection rates, or survival.
But it was associated with high adverse events to sirolimus ended with its discontinuation
3- with alemtuzumab as induction
C. CNI tapering until discontinuation
1. CNI withdrawal from azathioprine and steroid regimen . CNI withdrawal was associated with poorer graft function and graft survival.
2. CNI withdrawal from mycophenolate mofetil and steroid regimen in patients with or without renal dysfunction showed improvement in GFR in both cases but increased acute rejection episodes at 6 month in patients with stable renal function
3. CNI withdrawal from sirolimus based regimen was associated with better GFR at 1 year and 2 year .
D.CNI conversion
1- Late after transplant to mTOR inhibitor if GFR > 40 mL/min and urine protein to creatinine ratio ≤ 0.11 lead o better graft survival
1- early after transplant by month three and steroids stopped by month 8 was associated with higher acute rejection episodes and sirolimus side effects but with better renal function
.
3. Which is more feasible, calcineurin inhibitor-sparing or minimization and why? CNI minimization is more feasible as CNI is the main immunosuppression and sparing it can increase the risk of acute and chronic rejection
4. Give examples of calcineurin inhibitor-minimization protocols. ) CNI minimization with alemtuzumab as induction
CNI reduction by the use of m TOR
CNI reduction by the use of MMF
The use of CNIs led to decrease in incidence of AR and improved 1 year graft survival but couldn’t improve the long term allograft survival due to their nephrotoxicity, so different approaches tried to spare or avoid CNI using MMF, sirolimus, everolimus or belatacept.
Long term use of CNI leads to chronic nephrotoxicity with histologic features including interstitial fibrosis, tubular atrophy and microcalcification so several attempts have been done to decrease or avoid the use of CNI
CNI avoidance from the beginning:
CNI avoidance without alternative was ineffective and led to AR in some patients and the high dose of MMF wasn’t tolerated by some patients
Use of de novo sirolimus instead of CNI
Studies showed that de novo use of sirolimus was associated with better graft function when compared with cyclosporine.
The Elite symphony study showed that Tacrolimus had higher GFR at 1 year and lower rate of BPAR while sirolimus had worse allograft survival with more adverse events.
A meta analysis of 16 RCT suggested that de novo use of mTORi was associated with increased rate of graft failure
Another concern of de novo use of mTORi is the delayed wound healing
CNI avoidance with Belatacept
Phase II study showed that belatacept groups had higher GFR with less incidence of chronic allograft nephropathy but at 5 years caused more episodes of BPAR than cyclosporine group
BENEFIT study also showed that belatacept had lower incidence of chronic allograft nephropathy but with higher incidence of BPAR at 1 and 3 year follow up while at 7 year belatacept had lower risk of graft loss with better graft function
The main risk of belatacept was the PTLD
One study compared switching to belatacept versus continuing on cyclosporine and at 1 year, belatacept had significant higher GFR
CNI minimization is more feasible as will decrease the nephrotoxic effect of CNI with less risk of AR
Calcineurin inhibitor minimization with MMF:
Studies showed that it was effective, rate of BPAR and graft survival were the same as with standard CNI dose and GFR improvement was insignificant, but those studies had short term follow up
CNI minimization with mTORi:
Studies showed that everolimus with reduced exposure cyclosporine compared to standard exposure cyclosporine had same efficacy & renal function over 2 years but with higher incidence of adverse events
CNI minimization with alemtuzumab:
The 3C study showed that alemtuzumab based treatment with low dose Tac had less incidence of BPAR than basiliximab based treatment with standard dose Tac
CNI withdrawal from azathioprine and steroid regimen:
dual immunosuppression with azathioprine and steroid was associated with high risk of AR but no long term follow up was available
CNI withdrawal from MMF and steroid regimen:
A study showed that in patients with stable renal function, cyclosporine withdrawal was associated with significant improvement of kidney function but with increased rate of acute rejection at 6 months
in patients with deteriorating kidney function, a study showed that CNI elimination was associated with significant increase in GFR with the same rate of AR
CNI withdrawal from sirolimus based regimen:
studies showed that it was associated with better GFR and graft survival at 12 and 48 months but these results may be due to synergistic nephrotoxic effects which decrease on cyclosporine withdrawal causing improvement of kidney function
late after transplant:
studies suggested that conversion to sirolimus should be before significant renal impairment and proteinuria
early after transplant
studies showed that early conversion to sirolimus had significantly better renal function
3.Calcinueurin inhibitor feasibility sparing versus minimization ; calcineurin inhibitor-sparing is not feasible due to ; a) 48% acute rejection( Vincenti and associates 11), b) high rates of BPAR and lower graft survival ( ELITE-SYMPHONY), (ORION study) , c) high rates of adverse events and greater rate of treatment failure( ELITE-SYMPHONY), d) Increase rate of graft failure( Meta-analysis of 16 RCT comparing mTORI & CNI based regimens)
4.Calcineurin inhibitor minimization ;
Calcineurin inhibitors made a revolution in the transplantation by lowering the incidence of rejection compared to the previous decade. With their efficacy, some limitations were side effects of CAI’s including histologic features of renal injury like striped interstitial fibrosis, tubular atrophy, medial arteriolar hyalinosis, and tubular microcalcifications.
Calcineurin avoidance was shown to be ineffective in terms of the prevention of rejection. as shown in the ELITE-SYMPHONY study the eGFR at end of the first year posttransplantation was higher in the tacrolimus arm. In the Orion study the CNI free arm was removed because of the increased high rate of BPAR. many studies showed denovo m-TOR inhibitors as risky compared to CNI based regimens.
with the newer drug (Betalacept) non-inferiority was shown. In the BENEFIT-EXT study this was shown up to 7 years. the main concern with Betalacept was PTLD, especially this is a concern in EBV negative recipients.
CNI minimization was comparable to standard dose but still, no definite lower trough lecel is proved. the studies of CAI minimization with Alemtuzumab are difficult to conclude because of study designs but alemtuzumab-based induction had good results in terms of biopsy-approved acute rejection.
CAI withdrawal studies should be evaluated carefully. For example the sirolimus-cyclosporin regimen is toxic as we need to optimize dose because of the synergistic effect. In the MMF based regimen despite near future improvement in eGFR, this is overcome by increased acute rejection (net result is negative; favoring continuing CAI).
ın terms of CAI conversion, late conversion to siruliömus was associated with increase in proteinuria.
we have to take into consideration that late graft dysfunction is not merely CAI associated nephropathy.
Please summarise this article.
The balance between having the maximum benefit of CNI versus having less side effect is difficult . CNI toxicity eventually end with graft loss while less doses are associated with rejection. The introduction of MMF, mTORi and belatacept have introduced the concept of CNI sparing regimens
CNI conversion to sirolimus due to adverse effects other than nephrotoxicity like squamous cell carcinoma who had lead to significant delay in the median time to recurrent squamous cell carcinoma over a 2-year follow-up
Potential Complications with CNI Sparing Strategies
1- the mTORi reduce nephrotoxicity when used within the first year after transplant, but lead to intolerable side effects .
2- . Belatacept need longer follow to assess long-term patient outcomes.
3- Removal of a CNI improve renal function but this does not necessarily affect preexisting histologic lesions that can continue to progress over time
What are the different approaches calcineurin inhibitor-sparing immunosuppression?
A.CNI avoidance;
1- Using induction with daclizumab or antithymocyte globulin with complete avoidance of CNI was associated with high acute rejection rate
2- Using mTOR with antimetabolite and steroid gave comparable results to cyclosporine but inferior than tacrolimus (ELITE-SYMPHONY study). sirolimus with low dose tacrolimus have better result than complete avoidance of CNI
3- CNI avoidance with belatacept is comparable to cyclosporine but with more AMR later on . Switching from CNI-based regimen to a belatacept-based regimen after more than 6 months but less than 36 months after transplant
B.CNI minimization
1- with mycophenolic mofetil . There was no difference after 2 year between fixed-dose and the concentration controlled MMF doses so we can use concentration-controlled MMF in CNI sparing regimens.
2- with mTOR inhibitor showed no differences in renal function, rejection rates, or survival.
But it was associated with high adverse events to sirolimus ended with its discontinuation
3- with alemtuzumab as induction
C. CNI tapering until discontinuation
1. CNI withdrawal from azathioprine and steroid regimen
associated with high risk of acute rejection, but no solid data regarding long-term graft failure
2. CNI withdrawal from mycophenolate mofetil and steroid regimen in patients with or without renal dysfunction showed improvement in GFR in both cases but increased acute rejection episodes at 6 month in patients with stable renal function
3. CNI withdrawal from sirolimus based regimen was associated with better GFR at 1 year and 2 year but it could be due to the synergistic nephrotoxic effects
D.CNI conversion
1- Late after transplant to mTOR inhibitor if GFR > 40 mL/min and urine protein to creatinine ratio ≤ 0.11 lead o better graft survival
1- early after transplant by month three and steroids stopped by month 8 was associated with higher acute rejection episodes and sirolimus side effects but with better renal function
.
2-Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
Minimization is more feasible as it is associated with less rejection rate than the avoidance protocols.
3-Give examples of calcineurin inhibitor-minimization protocols.
CNI minimization with
1- mycophenolic mofetil plus daclizumab .
2- mTOR inhibitor
3- alemtuzumab as induction plus
a- half-level cyclosporine,no difference in rejection or graft loss 5 year ,
b- half-dose tacrolimus and no steroids 1 week after transplant. Acute rejection at 1 year was similar but higher chronic allograft nephropathy at 2 years
c- low-dose tacrolimus and MMF without steroids with low AMR after 6 month
CNI usage reduced AR incidence but not in long-term allograft survival.
This directly correlated with associated toxicities related to immunosuppressive effects.
CNI mode of action and adverse effects: it binds Calcineurin, competitively inhibiting
activated T cells. Inhibition of nuclear factor of activated T-cell dephosphorylation
prevents its translocation to the cell nucleus, leading to reduced expression of genes
required for T-cell activation such as interleukin.
Acute toxicities associated with CNIs include hypertension, tremors, and
seizures, thrombotic Microangiopathy, and renal dysfunction.
Tacrolimus is more commonly associated with glucose intolerance, tremor, and hair loss,
whereas hypertension, lipid abnormalities, and hirsutism are more common with
cyclosporine.
Tacrolimus may be less nephrotoxic; however, this remains controversial.
Chronic nephrotoxicity has been the main complication with long-term use of CNIs:
Histologic features include striped interstitial fibrosis, tubular atrophy, medial arteriolar
hyalinosis, and tubular micro calcification.
Calcineurin inhibitor-sparing strategies:
Calcineurin inhibitor avoidance:
Antibody induction, mycophenolate mofetil, and steroids.
Use of de novo Sirolimus.
Calcineurin inhibitor avoidance with newer drugs (belatacept):
Switching from CNI-based regimen to a belatacept.
Calcineurin inhibitor minimization.
Calcineurin inhibitor minimization with mammalian target of rapamycin
inhibitor immunosuppression
Calcineurin inhibitor minimization with Alemtuzumab
Calcineurin inhibitor withdrawal
Calcineurin inhibitor conversion :
Conclusion:
A)Calcineurin inhibitor-based immunosuppression remains the cornerstone of our current
immunosuppression protocols.
b) The current mainstay immunosuppression protocol is the one used in the ELITE-
SYMPHONY study (i.e., antibody induction, low-dose tacrolimus, MMF, and steroids)
c) Avoid use of Sirolimus de novo.
d) Some patients will benefit from conversion of tacrolimus to sirolimus at 6 months after
transplant; these patients should:
I. be low immunologic risk (exclude if loss of previous kidney transplant within 6
months not due to technical reasons and/or biopsy-proven acute rejection in the previous
1 month).
ii. have estimated GFR > 40 mL/min and no significant proteinuria (i.e., below 800
mg/day)
e) Some patients will benefit from belatacept this should be considered in patients
who have CNI nephrotoxicity, persistent acute tubular necrosis, or thrombotic
microangiopathy and who are unable to:
i. switch to sirolimus (early after transplant, acute tubular necrosis, thrombotic
microangiopathy, proteinuria, severe renal dysfunction)
ii. undertake CNI elimination (high risk of acute rejection [eg, < 6 months after
transplant], previous acute rejection, high immunologic risk [eg, more than 1B and DR
mismatch, donor-specific antibodies, highly sensitized; unable to tolerate high-dose
MMF, eg, at least 1500 mg/d.
Give examples of calcineurin inhibitor-minimization protocols.
This refers to using a lower dose of CNI.
CAESAR Study patient were treated with low-dose cyclosporine, MMF, and steroids;
standard, dose cyclosporine, MMF, steroids; or cyclosporine withdrawal (cyclosporine
tapered starting at month .
Calcineurin inhibitor minimization with mammalian target of rapamycin inhibitor
immunosuppression.
Calcineurin inhibitor minimization with Alemtuzumab.
1. Please summarise this article.
Calcineurin inhibitors (CNI), including cyclosporine and tacrolimus, use in kidney transplantation has been shown to be associated with improved short-term results with respect to graft function. But their long term use has been associated with hirsutism, hypertension, dyslipidemia, diabetes mellitus, tremors, alopecia, thrombotic microangiopathy, seizures and renal dysfunction. These side effects and non-adherence due to these side effects can lead to allograft dysfunction in patients on CNIs. CNI sparing strategies have been employed to tide-over these effects for a better graft outcome.
The CNI sparing strategies employed include:
A) CNI Avoidance: It involves use of immunosuppressants other than CNI in transplant patients. These protocols included:
1) Antibody induction with MMF and steroids: The results were disappointing with high acute rejection rates
2) De novo use of Sirolimus: Use of mTOR inhibitors de novo was associated with similar graft and patient survival as well as acute rejection rates and similar or higher GFR as compared to patients on CNIs. But the ELITE SYMPHONY trial showed that low-does tacrolimus had least acute rejection and best graft survival while sirolimus was associated with worst graft survival and highest rate of acute rejections. A meta-analysis concluded that mTOR inhibitor use increases the risk of graft failure by 43%
3) Use of Belatacept (co-stimulation blocker): Belatacept use has been shown to be associated with similar acute rejection rates in short-term, but higher rates on longer follow-up while the graft function has been shown to be better with decreased rates of chronic allograft nephropathy. The results have been similar even in extended criteria donors and high risk patients. Belatacept use has been associated with PTLD, hence should not be used in EBV negative patients.
B) CNI minimization: It involves reducing the dose of CNIs. The protocols used included:
1) MMF based: Studies with MMF based regime and CNI dose reduction were associated with increased rejection rates (ELITE SYMPHONY trial) as well as similar rejection rates (OPTICEPT trial) with similar graft function. Concentration controlled MMF use led to better results with respect to rejection, graft function and graft failure.
2) mTOR inhibitor based: mTOR inhibitor based CNI minimization led to non-inferior results but increased adverse events leading to increased rates of discontinuation of mTOR inhibitors.
3) Alemtuzumab use based: Induction with alemtuzumab and CNI minimization has shown lower rejection rates in short-term with similar graft function, graft and patient survival and rejection rates in long-term.
C) CNI withdrawal: It involves stopping CNI altogether. The protocols used include:
1) With Azathioprine and steroids: CNI withdrawal was associated with poorer graft function and graft survival.
2) With MMF and steroids: CNI withdrawal was associated with higher rejection rates but acute rejection was not increased in patients with graft dysfunction and there was increase in GFR in such patients.
3) With Sirolimus: There was no difference in patient and graft survival, better graft function but increased acute rejection rates were seen. But in patients with higher sirolimus levels, the acute rejection rates were similar with better graft function and survival.
D) CNI conversion: It involves changing CNI with another immunosuppressant (usually mTOR inhibitor) either as part of a protocol or due to adverse effects. It could be:
1) Early conversion (within 6 months post-transplant): It has been shown to be associated with better graft function, similar patient and graft survival, but increased risk of acute rejection, especially if steroids are discontinued. But higher adverse effects like diarrhea, aphthous stomatitis and acne led to increased drug discontinuation in mTOR inhibitor groups.
2) Late conversion (later than 6 months post transplant): It has been shown to be associated with better graft function and similar rejection and survival, in absence of proteinuria and with baseline GFR more than 40 ml/min.
3) Conversion due to non-renal adverse effects: CNI conversion due to malignancy has been shown to be associated with longer tumor-free period and delayed recurrence with stable graft function.
Considering the results of these studies, it is advisable to continue a CNI (especially tacrolimus), MMF and steroid based regime for 6 months and if the patient has eGFR more than 40, proteinuria less than 800 mg/day and is low risk (no history of graft loss within 6 months and no rejection in preceding 1 month), then CNI can be replaced with mTOR inhibitor. On the other hand, if patient has proteinuria, severe graft dysfunction, TMA, ATN occurring early after transplant, with high risk of rejection (highly sensitized, DSA positive, previous rejection of Banff >Ib, DR mismatch, not tolerating daily MMF dose of >1500 mg), then switching to belatacept is an option. But belatacept should not be used in EBV negative patients.
2. What are the different approaches calcineurin inhibitor-sparing immunosuppression?
The CNI sparing strategies employed include:
A) CNI Avoidance: It involves use of immunosuppressants other than CNI in transplant patients. The protocols which can be used include:
1) De novo use of Sirolimus: Use of mTOR inhibitors de novo was associated with similar graft and patient survival as well as acute rejection rates and similar or higher GFR as compared to patients on CNIs. But the ELITE SYMPHONY trial showed that low-does tacrolimus had least acute rejection and best graft survival while sirolimus was associated with worst graft survival and highest rate of acute rejections. A meta-analysis concluded that mTOR inhibitor use increases the risk of graft failure by 43%
2) Use of Belatacept (co-stimulation blocker): Belatacept use has been shown to be associated with similar acute rejection rates in short-term, but higher rates on longer follow-up while the graft function has been shown to be better with decreased rates of chronic allograft nephropathy. The results have been similar even in extended criteria donors and high risk patients. Belatacept use has been associated with PTLD, hence should not be used in EBV negative patients.
B) CNI minimization: It involves reducing the dose of CNIs. The protocols used included:
1) MMF based: Studies with MMF based regime and CNI dose reduction were associated with increased rejection rates (ELITE SYMPHONY trial) as well as similar rejection rates (OPTICEPT trial) with similar graft function. Concentration controlled MMF use led to better results with respect to rejection, graft function and graft failure.
2) mTOR inhibitor based: mTOR inhibitor based CNI minimization led to non-inferior results but increased adverse events leading to increased rates of discontinuation of mTOR inhibitors.
3) Alemtuzumab use based: Induction with alemtuzumab and CNI minimization has shown lower rejection rates in short-term with similar graft function, graft and patient survival and rejection rates in long-term.
C) CNI withdrawal: It involves stopping CNI altogether. The protocols which can be used include:
1) With MMF and steroids: CNI withdrawal was associated with higher rejection rates but acute rejection was not increased in patients with graft dysfunction and there was increase in GFR in such patients.
3) With Sirolimus: In patients with higher trough sirolimus levels, the acute rejection rates were similar with better graft function and survival.
D) CNI conversion: It involves changing CNI with another immunosuppressant (usually mTOR inhibitor) either as part of a protocol or due to adverse effects.
3. Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
De novo CNI sparing protocols are not feasible due to definitively better graft results in short-term with CNI based immunosuppression regime. But CNI conversion to mTOR inhibitors after 6 months is feasible, especially if the patient is low risk and has good graft function with no/low proteinuria. If there is graft dysfunction, CNI switch to belatacept can be done. Patients who cannot be switched to mTOR inhibitors can be continued on low dose CNI with maximally tolerated dose of MMF and steroids.
4. Give examples of calcineurin inhibitor-minimization protocols.
These include:
1) Low dose Tacrolimus with MMF and steroids (ELITE SYMPHONY trial)
2) Low dose Cyclosporine, MMF and steroids (CAESAR study)
3) Low dose Cyclosporine with concentration controlled MMF and steroids (OPTICEPT trial)
4) Low dose cyclosporine with Everolimus and steroids (A2309 study)
5) Low dose Tacrolimus and MMF with Alemtuzumab
6) Low dose cyclosporine with Alemtuzumab and steroids
1-Although CNIs improved acute rejection and graft survival, they have acute adverse effects and chronic nephrotoxicity. So, there is a need to have an approach balancing between beneficial and hazardous outcomes. Different regimens were tried.
2-CNI avoidance with use of mTOR was associated with increased graft failure rate .Replacement by belatacept was associated with GFR preservation but with increased episodes of BPAR.
-Using lower doses of CNI either de novo or following side effects ;CNI minimization, with MMF was found effective as proved by BPAR and graft survival, but with small GFR improvement, Studies in that regard were short term and lacking some data like ABMR ,staining for C4d and DSAs.
CNI minimization with mTOR was associated of CNI nephrotoxicity potentiation .CNI minimization with use of almetuzumab was found to have 58% reduction in BPAR,
Tapering of CNI fIn CONVERT study CNI was substituted by Sirolimus rom:
AZA and steroid regimen increased risk of acute rejection
MMF and steroid regimen was associated with improvement in GFR.
Sirolimus based regimen was associated with increased risk of AR but better Cr cl and blood pressure.
In CONVERT study, CNI was substituted by sirolimus with outcome of better renal function and lower graft loss in addition to significant delay in tumor recurrence.
3-It looks that minimization approach is more feasible as sparing approach is subjected to higher risk of graft loss.
4-CNI minimization with either MMF,mTOR or almetuzumab.
Since the implementation of CNI in the transplant IS protocols, the risk of rejection had been decreased, but there were no improvement in graft survival, this was attributed to the CNI nephrotoxicity. the introduction of other IS medication like MMF, mTORi, and belatacept has led efforts directed toward CNI minimization.
CNI sparing strategies include:
CNI avoidance:
complete omission of CNI usually planned de novo and involve the use of another IS.
Ab induction+ MMF+ Steroids:
studies showed increased risk of rejection necessitating reintroduction of CNI.
Use of de novo sirolimus:
In ELITE-SYMPHONY study, sirolimus use was associated with highest rate of biopsy proven acute rejection and lowest graft survival & more adverse effects and more treatment failure.
CNI avoidance with belatacept:
In BENEFIT study belatacept use associated with :
CNI Minimization:
Involves the use of low dose of CNI either planned de novo or due to side effects.
CNI minimization with MMF:
In CAESAR study, there were no difference in GFR at 12 months between patient groups( low dose cyclosporine, standard dose cyclosporine, cyclosporine withdrawal).
CNI minimization was effective with BPAR and graft survival was similar to those who received standard dose cyclosporine.
CNI minimization with mTORi:
In a large prospective trial, the patients received either evrolimus+ low dose cyclosporine or MMF+ standard dose cyclosporine. everolimus was associated with comparable efficacy and renal function to MMF but higher incidence of adverse effects.
CMI minimization with alemtuzumab:
studies shows no difference in a 5 year follow up of patients who received alemtuzumab versus patients who not.
In 3C study, alemtuzumab use was associated with 58% reduction in BPAR in 6 months post transplant
CNI withdrawal:
Tapering of CNI dose until eliminated. planned de novo or because of side effects.
CNI withdrawal from azathioprine and steroid regimen:
studies showed high risk of rejection.
CNI withdrawal from MMF and steroid regimen:
In stable renal function: improvement in renal function but increase rejection risk.
In deteriorating renal function: significant increase in GFR, no increment in rejection risk.
CNI withdrawal from sirolimus based regimen:
In a systematic review, withdrawal was associated with an increased risk of rejection, higher creatinine clearance and reduced blood pressure.
CNI Conversion;
CNI conversion to sirolimus should be done before significant renal damage occur( GFR > 40, no significant proteinuria) and is prefered at least 6 months post transplant, to patients of low immunological risk.
I think CNI minimization is more feasible than CNI avoidance as there is a significant risk of rejection with CNI avoidance and this risk was not reduced or canceled by the use of different induction agents or high doses of maintenance IS.
Since the introduction of CNI into the kidney transplantation practice and standardization of CNI based maintenance therapy in high risk kidney recipients, it was observed a significant reduction in the incidence of acute cellular rejections and graft failure.
CNI reduces the expression of genes required for T-cell activation such as interleukin 2. Based on large evidence, CNI are the cornerstone of maintenance immunosuppression. However, many side effects and adverse events are attributed to the use of CNI including nephrotoxicity.
To overcome the toxicities of CNI, alternative immunosuppressive regimens were evaluated. CNI minimization or sparing strategy is one of the approaches to avoid CNI related adverse events. However, owing to the potent immunosuppressive effect of CNI, reducing the dose or targeting lower therapeutic levels or even avoiding CNI could potentially cause acute rejection and allograft loss.
What are the different approaches of CNI-sparing immunosuppression?
There are several strategies in CNI sparing regimens:
1-Calcineurin inhibitor avoidance:
Complete omission of CNI is usually planned de novo and involves using another immunosuppressant drugs. Use of de novo sirolimus or Antibody induction followed by maintenance of CNI free regimen including mycophenolate mofetil, and steroids. Calcineurin inhibitor avoidance with newer drugs like Belatacept was also studied. All previously mentioned combinations were inferior to CNI base regimens, in term of acute rejection and allograft loss.
2-Calcineurin inhibitor minimization:
This refers to targeting lower therapeutic levels of CNI. This is usually planned de novo or doses are changed due to side effects/ adverse events.
Calcineurin inhibitor minimization with mycophenolic mofetil.
Some studies showed that ,CNI minimization seems to be effective, with BPAR and graft survival rates similar to that shown in patients who received standard CNI doses.
However, GFR improvements were only small and not significant. In addition, these studies had short-term follow-up and lacked data on antibody-mediated rejections, circulating donor-specific antibodies (DSAs), and staining for C4d in renal biopsy specimens.
Calcineurin inhibitor minimization with mammalian target of rapamycin inhibitor immunosuppression
Mammalian target of rapamycin inhibitors have been used in combination with CNI, but they can potentiate CNI nephrotoxicity when co administered with CNI.
Calcineurin inhibitor minimization with alemtuzumab
Studies showed that , Alemtuzumab-based induction treatment followed by low-dose tacrolimus and MMF without steroids at 6 months after transplant, had a 58% reduction in BPAR.
3-Calcineurin inhibitor withdrawal
This refers to tapering of CNI dose until eliminated.This is usually planned de novo or as a result of an adverse event .
Calcineurin inhibitor withdrawal from azathioprine and steroid regimen
This regimen is associated with increased risk of acute rejection
Calcineurin inhibitor withdrawal from mycophenolate mofetil and steroid regimen in patients with or without renal dysfunction This regimen has been attempted in patient with deteriorating renal function and it is found to be associated with increase in GFR .
The combination of cyclosporine and sirolimus increase the nephrotoxic effect of CNI, and it is not really surprising that removal of cyclosporine from regimens using CNI leads to improved renal function or allograft histology.
Calcineurin inhibitor withdrawal is associated with an increased risk of acute rejection.
4-Calcineurin inhibitor conversion
Calcineurin inhibitors conversion to m-TORi was the subject of several studies in low and high risk patients.Results ofstudies showed that conversion to m-TORi in high risk patients is associated with increased risk of rejection and graft loss.
Summary:
Cyclosporine and tacrolimus have been added to immunosuppressive regimens for kidney transplantation, resulting in significant decreases in acute rejection and improvements in 1-year graft survival. But this hasn’t translated into better long-term allograft survival.
Immunosuppressive drugs have side effects that are connected to their immunosuppressive effects.
Moreover, each medicine has its own toxicities. Immunosuppressive minimizing strategies addressed both toxicities. Calcineurin inhibitors are linked to chronic nephrotoxicity, and calcineurin inhibitor sparing methods have been utilized to improve long-term results. However, in the last decade or so, it has become clear that calcineurin inhibitor nephrotoxicity is not the main cause of late graft failure. Many late transplant losses are now attributed to persistent immunological damage caused by donor-specific antibodies. However, some individuals may have late allograft loss due to chronic or subacute immune-mediated damage. Weak donor-specific antibody profiles have not been examined in most calcineurin inhibitor sparing trials. One of the most difficult tasks is determining which patients would benefit from this method.
What is calcineurin inhibitor-sparing immunosuppression?
1-Calcineurin inhibitor avoidance; This is normally done de novo with another immunosuppressant. A meta-analysis of 16 randomized controlled studies found that using mTOR inhibitors as de novo treatment increased graft failure.
2-Newer medicines avoid calcineurin inhibitors (belatacept)
Belatacept was related to GFR preservation for up to 5 years, but with more BPAR events.
Calcineurin inhibitor lowering
Using a lower dosage of CNI. This is generally planned or triggered by an occurrence.
Early after transplant conversion
Multiple studies have shown that early sirolimus or cyclosporine conversion improves renal function.
Chronic antibody-mediated rejection may be the major cause of late graft failure, either owing to non-compliance or the presence or absence of DSA.
Calcineurin inhibitor removal from sirolimus-based therapy enhanced renal function at 1 year, and improved graft survival and GFR at 2 years, according to Mulat et al.
Conversion of calcineurin
Withdrawal of CNI with Sirolimus reveals improvement of renal function if GFR is over 40 ml/min and no proteinuria.
Calcineurin inhibitor minimization is more practical, especially for low immunological risk patients. we will decrease the side effects of CNI(interstitial fibrosis, metabolic disorders) with an acceptable risk of rejection.
Give examples of calcineurin inhibitor-minimization protocols.
CNI minimization with alemtuzumab
CNI reduction by the use of m TOR
CNI reduction by the use of MMF
Please summarise this article.
CNI as an immunosuppressant in kidney transplant has been associated with substantial reductions in the incidence of acute rejection with a subsequent improvement in 1year graft survival . Acute toxicities associated with CNIs include hypertension, tremors, seizures, thrombotic micro – angiopathy, and renal dysfunction. Chronic nephrotoxicity has been the main complication with long-term use of CNIs. Unfortunately, we do not have reliable tests to quantify the level of immuno – suppression achieved cumulatively or even for single drugs. Immunosuppressive minimization strategies try to address both the overall immunosuppressive effect common to all of these agents and toxicities uniquefor the compound. By reducing immunosuppression, we can reduce or eliminate these toxicities; however, any such strategy has the potential for underimmuno – suppression and consequently acute or chronic rejection and potentially premature graft loss and death. In view of this, although some patients do benefit from CNI-sparing approaches, others may have late allograft loss from chronic and sub acute immune mediated injury. One of the biggest challenges that we face is to be able to distinguish who benefits from this strategy and who will not.
What are the different approaches calcineurin inhibitor-sparing immunosuppression?
1-Calcineurin inhibitor avoidance; Complete omission of CNI is usually planned de novo and involves using another immuno – suppressant . A meta-analysis of from 16 randomized controlled trials suggested that the use of an mTOR inhibitor as de novo therapy was associated with an increased rate of graft failure.
2-Calcineurin inhibitor avoidance with newer drugs (belatacept)Studies showed that ,belatacept is associated with GFR preservation for up to 5 years ,although it resulted in more episodes of BPAR.
3-Calcineurin inhibitor minimization
This refers to using a lower dose of CNI. This is usually planned de novo or as a result of an adverse event .
Calcineurin inhibitor minimization with mycophenolic mofetil Some studies showed that , CNI minimization seems to be effective, with BPAR and graft survival rates similar to that shown in patients who received standard CNI doses. However, GFR improvements were only small and not significant. In addition, these studies had short-term follow-up and lacked data on antibody-mediated rejections, circulating donor-specific antibodies (DSAs), and staining for C4d in renal biopsy specimens.
Calcineurin inhibitor minimization with mammalian target of rapamycin inhibitor immunosuppression Mammalian target of rapamycin inhibitors have been used in combination with CNI, but they can potentiate CNI nephrotoxicity when co administered with CNI.
Calcineurin inhibitor minimization with alemtuzumab Studies showed that , Alemtuzumab-based induction treatment followed by low-dose tacrolimus and MMF without steroids at 6 months after transplant, had a 58% reduction in BPAR.
4-Calcineurin inhibitor withdrawal
This refers to tapering of CNI dose until eliminated.This is usually planned de novo or as a result of an adverse event .
Calcineurin inhibitor withdrawal from azathioprine and steroid regimen;
This regimen is associated with increased risk of acute rejection as seen in meta analysis.
Calcineurin inhibitor withdrawal from mycophenolate mofetil and steroid regimen in patients with or without renal dysfunction This regimen has been attempted in patient with deteriorating renal function and it is found to be associated with increase in GFR .
Calcineurin inhibitor withdrawal from sirolimus based regimen The combination of cyclosporine and sirolimus has synergistic nephrotoxic effects, and it is not really surprising that removal of cyclosporine from regimens using both cyclosporine and sirolimus leads to improved renal function or allograft histology Calcineurin inhibitor withdrawal is associated with an increased risk of acute rejection but higher creatinine clearance and reduced blood pressure.
.
5-Calcineurin inhibitor conversion
This refers to replacing CNI with another immunosuppressant. This is usually a result of an adverse event but can be planned de novo.
Conversion late after transplant In CONVERT study , substitution the CNI for sirolimus is found to be associated with better renal function, and had lower graft loss in patients with baseline GFR > 40 mL/min and urine proteinto-creatinine ratio ≤ 0.
Conversion early after transplant studies showed that, early conversion from CNI to sirolimus is associated with better Glomerular filtration rate and higher rate of acute rejection .
Calcineurin inhibitor conversion to sirolimus due to adverse effects other than nephrotoxicity conversion of CNI to sirolimus is associated with significant delay in the median time tumour recurrence .
Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
Calcineurin inhibitor minimization is more feasible, because by reducing immune suppression , we can reduce or eliminate toxicities . however, any such strategy has the potential for under immuno – suppression and consequently acute or chronic rejection and potentially premature graft loss and death. Although some patients do benefit from CNI-sparing approaches, others may have late allograft loss from chronic and sub acute immune mediated injury. One of the biggest challenges that we face is to be able to distinguish who benefits from this strategy and who will not.
Give examples of calcineurin inhibitor-minimization protocols.
1-calcinurin inhibitor minimization with mycophenolic mofetil .
2-calcinurin inhibitor minimization with mammalian target of rapamycin inhibitor immunosuppression .
3-calcinurin inhibitor minimization with alemtuzumab .
1. Please summarise this article.
Although CNI , cyclosporine and tacrolimus reduced the incidence of acute rejection and improved graft survival , it’s nephrotoxicity and the evolving of non nephrotoxic immunosuppressive medications lead to the trend of having CNI sparing regimens .
CNI mode of action is binding to immunophilins leading to inhibition of nuclear factor of activated T-cell dephosphorylation, leading to reduced expression of T-cell activation genes such as interleukin 2.
Concerning their side effects Tacrolimus is more commonly associated with glucose intolerance, tremor, and hair loss, but is less nephrotoxic than cyclosporine which is more common to cause hypertension, lipid abnormalities, and hirsutism.
Calcineurin inhibitor-sparing strategies
Some studies tried using induction with dacluzimab or antithymoglobulin and maintenance with steroids and MMF without replacing CNI with another immunosuprresive.
Other studies compared between the use of sirolimus and the used of cyclosporine each one with azathioprine and steroids revealing acute rejection rates with higher GFR with Sirolimus , also Kris etal showed similar results with MMF .
Flechner et al demonstrated that sirolimus group had better renal function and it reduced the occurrence of chronic allograft nephropathy when compared with cyclosporine both groups received basiliximab, MMF 2 g/day, steroids.
Another study revealed chronic vascular changes in the protocol biopsies of tacrolimus cases compared with sirolimus cases
The ELITE-SYMPHONY study manifested the different outcomes and safety of 4 immunosuppressive regimens , with one of them CNI free and stated that graft survivals higher and rejection was lower in the tacrolimus group in comparison to others.
In the SPIESSER Trial, there was no variation regrading graft survival and BPAR between groups with and without CNI , GFR was higher in Sirolimus group.
Multiple studies concluded that m TOR denovo therapy and CNI free regimens are associated with increased risk of graft failure.
Belatacept a cytotoxic T lymphocyte-associated antigen 4 immunoglobulin was as efficient as cyclosporine in prevention of acute rejection at 6 months, with higher GFR than the cyclosporine group.
BENEFIT study showed that more or less intense betalacept doses are associated with lower incidence of chronic allograft nephropathy than cyclosporine but with higher incidence of BPAR.
Calcineurin inhibitor minimization with MMF
CAESAR Study revelaed that cyclosporine withdrawal is associated with high rates of BPAR.
Low dose tacrolimus is associated with less acute rejection rate at 1 year.
The Opticept Trial mentioned that concentration-controlled MMF can be used in CNIsparing regimens.
Calcineurin inhibitor minimization with m TOR
Although being an efficent combination it can enforce nephrotoxicity and has adverse effects.
Calcineurin inhibitor minimization with alemtuzumab
Compared to basiliximab-based induction followed by convetional tacrolimus, MMF, and steroids showed a 58% reduction in BPAR
Calcineurin inhibitor withdrawal from azathioprine and steroid regimen
was associated with increased rejection risk but graft failure was not affected on the long term as shown by multiple studies.
Calcineurin inhibitor withdrawal from MMF and steroid regimen in cases without renal dysfunction showed improvement of renal function and increased acute rejection rate at 6 months
The same regimen was applied to cases with renal dysfunction and showed no increased incidence of acute rejection and improvement in GFR
Calcineurin inhibitor withdrawal from sirolimus based regimen
showed by a study better renal function at 1 year, at 2005 another study showed after 2 years that graft survival and GFR was better with CNI withdrawal,
Mulat et al mentioned that CNI withdrawal is associated with increased acute rejection and improved renal function.
Calcineurin inhibitor conversion
Can be done late by using m TOR during CNI withdrawal revealing improvement of renal function with Sirolimus if GFR is above 40 ml/min and with no proteinuria.
Conversion early after transplant
Multiple studies demonstrated that early conversion of CNI to sirolimus or cyclosporine to everolimus is accompanied with improved renal function.
Late graft failure may not be caused by CNI toxicity but chronic antibody mediated rejection can be the main cause either due to lack of compliance or due the presence or denovo ocuurence of DSA
CNI-sparing strategies increased the occurrence of acute or chronic antibody-mediated rejection
2-What are the different approaches calcineurin inhibitor-sparing immunosuppression?
-induction with dacluzimab or antithymoglobulin and maintenance with steroids and MMF without replacing CNI with another immunosupressive.
-sirolimus , azathioprine and steroids
-sirolimus ,MMF and steroids
-Basilimab , sirolimus ,MMF and steroids
– ELITE-SYMPHONY study Dacluzimab, sirolimus ,MMF and steroids , low dose cyclosporine ,low dose tac or sirolimus
-rATG sirolimus ,MMF ,steroids
-mTOR and MMF with increased incidence of graft failure.
-Basiliximab , less and more intensive betalacept,MMF and steroids
– switching to betalacept
3-Which is more feasible, calcineurin inhibitor-sparing or minimization and why?
CNI minimization is more feasible as CNI is the main corner stone of immunosuppression and sparing it can increase the risk of acute and chronic rejection
4-Give examples of calcineurin inhibitor-minimization protocols.
CNI minimization with m TOR
CNI minimization with MMF
CNI minimization with alemtuzumab
Since introduction of CNI the incidence of AR is decreasing but long-term graft survival is not improved, which may be due to CNI nephrotoxicity. Using of drugs not causing nephrotoxicity as MMF, mTOR-I, & belatacept leading to CNI sparing regime.
Acute CNI nephrotoxicity manifested as hypertension, tremor, seizure, TMA & renal dysfunction. Chronic CNI nephrotoxicity characterized histologically by striped interstitial fibrosis, tubular atrophy, medial arteriolar hylinosis & tubular micro calcification.
CNI sparing regime include:
(A) CNI- avoidance:
(B) CNI withdrawal:
mean tapering of CNI dose until elimination of CNI ( this done either to reduce side effects or de novo.
(C) CNI conversion:
Most trials of CNI sparing regime had short-term follow-up & DSA monitoring was not done.
CNI minimization: mean using of low dose CNI de novo or reduce the CNI dose due to side effects. It include:
Conclusion: CNI minimization regimes may reduce nephrotoxicity but may increase acute & chronic rejection rate leading to early graft loss. CNI nephrotoxicity is not considered major cause of late & chronic rejection, but the DSA is the major contributor of rejection. The study recommend the following: