m-TOR-I are immunosuppressive drugs inhabiting signal 3 of lymphocyte proliferation ,members of this group are:everolimus and sirolinus
Immunosuppressive protocols containing mTOR-I are generally effective in :
1)-low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols. However, we have limited reports on their efficacy in high-risk groups.
2)-malignancies,
3)-encapsulating peritoneal sclerosis
4)- BK
5)- CMV virus infections.
They were shown to have unacceptable side effect profile leading to high discontinuation rate. E.g priteinuria ,hyperlipidemia These might have contributed to their reduced popularity (both as early and maintenance) in the recent years. Moreover there is a new concern linking their use to increased patients’ mortality. More studies, looking into the safety of mTOR-I, are needed.
saja Mohammed
3 years ago
mTOR inhibitors like everolimus and sirolimus is mammalian target of rapamycin act on signal 3 inhibtion of T-Cell activation its used mainly as maintenance immunosuppressive therapy since the last two decades mainly in low immunological risk as CNI sparing agent or early CNI conversion , de-novo use or CNI minimization protocols in many studies with comparable results in regards of graft and patient survival and better renal function compared to CNI protocol but as per systematic review and meta-analysis studies confirmed that the use of mTOR inhibitors with CNI minimization or elimination associated with higher BPAR rate without effect on mortality or graft or patient survival rate with better glomerular filtration rate compared to CNI based protocol , recent prospective trails comparing the use of m TOR PLUS MMF combination compared to CNI tacrolimus plus MMF protocol which conclude both are effective with similar graft and patient survival .
few studies address the efficacy of MTOR I in high immunological risk recipients and recipients with ECD with short follow up of 12 months in most of the studies which shows comparable results to CNI based IS but more side effects with the use of mTOR I Like myelosuppression ,mouth ulcerations metabolic effect with hypertriglyceridemia and hyperlipidemia , protineuria with infections like wound infection , CMV , POST transplant Peritoneal sclerosing fibrosis , Interstitial pnemonitis
still its preferred immunosuppressive agent in specific group of kidney transplant patients like those with malignancy, BK, cmv infections
still, we need more large studies to assess the long-term efficacy of the m TORI in the kidney transplant field.
Ben Lomatayo
3 years ago
mTMORI was introduced to the field of transplantation over the 20 years. Its has been used mainly in low risk patients under different therapeutic strategies. The ideal candidates for mTORI are ; a) low immunologic risk, b) malignancies, c) encapsulating peritoneal fibrosis, d) BKV nephropathy, e) CMV infections. The protocols for using for using mTORI includes ; CNI avoidance, CNI minimization , and CNI withdrawal. The mechanism of action is through inhibition of signal-3 of T cell activation.. Several studies demonstrated comparable allograft rejection rejection rate, and better renal function in comparison t o standard CNI protocols. The use of mTORI allowed minimal doses of CNI which is beneficial in decreasing side effect of CNI without jeopardising allograft function. mTORI has been tried as well in high risk in small scale with mixed results. Although mTORI is associated with 40% decrease in malignancy and 56% decrease in non-melanoma skin cancer, there is a recent concern about risk of mortality(105). The drug was discontinued in up to 53.2% due to proteinuria, primary glomerulonephritis, and poor graft function(106). Another problem is GI side effects which significantly associated with poor quality of life(107). Regarding the cost of treatment, some studies showed low cost for sirolimus treated group(104). Currently small numbers of patients are on mTORI(low risk) compared to larger numbers on CNI specially tacrolimus. Most of the studies addressing the mTORI are short studies, there studies are needed to evaluate the long-term effect on the drug over long run.
Assafi Mohammed
3 years ago
Use of mTORi have been studied by many researchers to replace CNIs and to minimize the chronic nephrotoxicity of CNIs.
Many studies reported comparable graft rejection rate and a better kidney function with the use of mTORi.
mTORi have been used in the renal transplantation as de novo or when being converted to after strategies avoiding or minimizing CNIs.
mTORi have been associated with promising outcome in renal Transplantation when being converted to in specific situation as malignancy or appearanc of adverse effects precluding continuation of CNIs.
mTORi have been associated with increased incidence of proteinuria and poor wound-healing.
Mohammed Sobair
3 years ago
mTOR-I used in kidney transplant for longtime.
They have been used in different combination immunosuppressant for low risk group
renal transplantation.
used in the various state:
CNI-free protocols: either as De novo regiments, or by conversion from CNIs at a later
stage.
Many studies reported comparable graft rejection rate and a better kidney function
compared to standard CNI protocols.
mTOR-I when used in combination with CNIs:
Facilitated the use of lower doses of CNIs with the resultant reduction of CNI related
side effects, without seriously compromising graft outcome.
Recipients of kidneys from extended-criteria transplantation.
However, only few reports studied their use in high risk group renal transplantation, with
variable outcomes.
A drop in their popularity in the recent years, and their use was associated with multiple
adverse events, in addition to a recent concern of their link to increased mortality.
Also, a high discontinuation rate was demonstrated across many of the studies available
to date.
Mahmud Islam
3 years ago
In this comprehensive review thoroughly summarized the mTOR-I’s, one can conclude that the backbone of the immune suppression in renal transplant patients is CNIs (primarily Tacrolimus). mTOR inhibitors were found effective, non-inferior, etc when the replaced MMF not CNIs in most of the studies. except for some indications like malignancy and intractable side effects of CNIs mTOR inhibitors are very helpful in maintaining the immune suppression and prevention of acute rejection.
Ahmed Omran
3 years ago
mTOR inhibitors inhibit T&B cells ,fibroblasts, vascular smooth muscles and some malignant cells. They include everolimus (better bioavailability) and everolimus. Their level monitoring is mandatory as they have narrow therapeutic range .There are also several drug-drug interactions with hepatic metabolism with CYTP450.Due to synergistic drug-drug interaction with cyclosporine ,dose reduction of both drugs is needed in case of concomitant use. Based on this, several protocols were adopted including CNI avoidance, minimization and conversion; either early or late.
Beneficial effects of mTOR
.Antiproliferative effect decrease risk of malignancy including skin cancers
.Less risk of opportunistic infections
.Better GFR and decreased risk of CAN.
Adverse effects
Delayed wound healing, increased risk of rejection ,non opportunistic infection ,podocytopathy ,hepatitis mouth ulcers ,pneumonitis, bone marrow suppression, PTDM ,and increase all-cause mortality among others.
mTOR inhibitors have place in low risk with advantage of better GFR than conventional protocols .Also ,they have advantage in certain situations including malignancies, encapsulating peritoneal sclerosis, BK and CMV viral infections. However ,their use is limited by side effects and possible increased mortality.
Dalia Eltahir
3 years ago
What is the current position of m-TOR Inhibitors in Kidney Transplantation? Mammalian target of rapamaycin inhibitors (mTOR-I) has been in use in kidney transplantation in different combination with immunosuppressant for low risk group mTOR binds to FK protein but would not inhibit calcineurin. Their complex with calcineurin binds to rapamycin target and inhibit signal 3 of T-cell activation, through inhibition of cytokines activating T-cell cycle .
CNI-free protocols, either as De novo regiments, or by conversion from CNIs at a later stage.
– combination with CNIs, result in reduction of CNI related side effects, without affecting the graft outcome.
– Patient with certain conditions like malignancy, post-transplant encapsulating peritoneal scelorosis, CMV and BK virus infections.
– protocols containing mTOR-I showed comparable results to standard protocols among recipients of kidneys from extended-criteria transplantation.
-Their use in high risk group renal transplantation is reported to be associated with variable outcomes. Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation; Immunosuppressive protocols containing mTOR-I are generally effective in low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols. High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols; Immunosuppressive protocols containing mTOR-I have limited reports on their efficacy in high-risk groups with variable outcome . Safety of mTOR-I Protocols in Kidney Transplantation; Side effects include, GI symptoms , poor wound healing , hyperlipidaemia and worsening proteinuria . Using mTOR cause reduction of malignancy {non-melanoma skin cancer } .
Hinda Hassan
3 years ago
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
The mTOR-I ( sirolimus and evarolimus) binds to FK protein inhibiting signal 3 of T-cell activation.
Use of mTOR-I Among Low/ standard Risk Renal Transplantation:
· In CNI avoidance with De novo m TOR-I introduction
· Conversion from CNI into mTOR-I preserve eGFR and help to spare CNI with good graft survival and variable rejection rate .
· In CNI avoiding regimen sirolimus showed similar result to CNI based regimen at one year, regarding patients’ survival, graft survival, eGFR and acute rejection .
Sirolimus cause more dyslipidaemia, oedema, proteinuria and mouth ulcer.
Using mtor with CNI elimination have significantly more rejection, without increasing patient mortality or graft loss, and a better eGFR compared to the standard CNI protocols while with CNI minimization ,there are similar graft rejection compared to the standard CNI protocols .
Few studies are available. Sirolimus was comparable to azathioprin in cyclosporine based regimen and with MMF in CNI based regimen. Other studies contradict this but the difference was non-significant
The cost of treatment
The cost of treatment and graft loss were compared among 4 groups: early sirolimus+ withdrawal of
steroids/CNI, early transition by sirolimus, early transition by everolimus, and the standard prednisolone, MMF and CNI. The lowest cost was for early sirolimus transition group .
Safety of mTOR-I Protocols in Kidney Transplantation
Using mTOR cause 40% reduction of malignancy and 56% reduction of non-melanoma skin cancer, but there is high risk of mortality and adverse reactions leading to discontinuation of their use reaching to 53.2%. These reactions included Proteinuria, primary glomulonephritis, poor graft function and GIT discofort.
Amit Sharma
3 years ago
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
mTOR inhibitors: The mammalian target of rapamycin (mTOR) inhibitors are immunosuppressants sirolimus and everolimus which inhibit T cell proliferation. These drugs, in addition to their effect on immune system, also have anticancer properties, antiviral action (against BK virus and CMV) as well as cardiovascular protective effects like inhibition of intimal proliferation and action on atherosclerotic plaque. Due to the nephrotoxic action of calcineurin inhibitors (CNI), mTOR inhibitors have been used in kidney transplantation.
Different mTOR inhibitor based protocols: mTOR inhibitors have been used both as de novo as well as conversion to CNIs or addition to CNI based regimen with CNI minimization.
A) 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%
B) mTOR inhibitor based CNI minimization: mTOR inhibitor based CNI minimization led to non-inferior results but increased adverse events leading to increased rates of discontinuation of mTOR inhibitors.
C) CNI conversion: Changing CNI with 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. Role of mTOR inhibitors in transplantation: Considering the results of these studies, it is advisable to continue a CNI (especially tacrolimus), MMF and steroid based regime for 3 to 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, no DSA), completely healed wound, no risk of recurrence (basic disease causing ESRD is not glomerulonephritis) and well-tolerating antiproliferative agents, then CNI can be replaced with mTOR inhibitor.
Abdulrahman Ishag
3 years ago
What is the current of MTOR inhibitor in kidney transplantation
mTOR-I, comprised of sirolimus and evarolimus, binds to FK protein but would not inhibit calcineurin. Their complex with calcineurin binds to rapamycin target and inhibit signal 3 of T-cell activation, through inhibition of cytokines activating T-cell cycle .
mTOR-inhibitor have been used in the following ; – In different combination immunosuppressant for low risk group renal transplantation. – In various CNI-free protocols, either as De novo regiments, or by conversion from CNIs at a later stage. – In combination with CNIs, facilitated the use of lower doses of CNIs with the resultant reduction of CNI related side effects, without seriously compromising graft outcome. – In certain group of renal transplant recipients, including those with malignancy, post-transplant encapsulating peritoneal scelorosis, CMV and BK virus infections. – protocols containing mTOR-I showed comparable results to standard protocols among recipients of kidneys from extended-criteria transplantation. -Their use in high risk group renal transplantation is reported to be associated with variable outcomes.
Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation; Immunosuppressive protocols containing mTOR-I are generally effective in low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols. High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols;
Immunosuppressive protocols containing mTOR-I have limited reports on their efficacy in high-risk groups.
Safety of mTOR-I Protocols in Kidney Transplantation; Immunosuppressive protocols containing mTOR-I have unacceptable side effect profile leading to high discontinuation rate and these including infection , GI symptoms , poor wound healing , hyperlipidaemia, deceased sperm count in males on sirolimus and worsening proteinuria . Moreover there is a new concern linking their use to increased patients’ mortality.
.
Doaa Elwasly
3 years ago
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
Maintenance immunosupressive treatment includes mTOR-I, consisting of sirolimus and evarolimus,
Its mode of action is by binding to FK protein then make complex with calcineurin which binds to rapamycin target and inhibit signal 3 of T-cell activation, .
It’s advantage is that it can lead to reduction of malignancy, mainly non-melanoma skin cancer and accompanied with lesser CMV viremia , and had positive effect in BK viremia/BK associated nephropathy and post-transplant encapsulating peritoneal sclerosis, on the other hand studies mentioned that it was associated with an increased risk of mortality. Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation
Some studies assessed CNI avoidance with De novo m TOR-I introduction, or shifting from CNI into mTOR-I .
mTor I with low dose CNI showed good graft survival and low rejection rate
Everolimus with CNI elimination led to increased rejection risk , without increasing patient mortality or graft loss, and a better eGFR.
when mTOR-I replaced CNI , the rejection rate was similar, lower creatinine and more marrow suppression; when substituted antimetabolites there was less rejection and lower CMV infection but higher hyperlipidaemia.
mTOR-I combination with CNI graft and patient survival were similar in different immunosuppressive strategies .
Patients on low dose mTOR-I had more rejection and better eGFR compared to the high dose with similar CNI doses. High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols
mTOR-I is as good as other standard protocols among recipients of extended-criteria donors.
MMF was substituted by everolimus with low dose CNI, and there was no increased rejection at three months in a study.
mTOR-I showed acceptable results among high immunologic risk cases.
Withdrawal of mTOR-I could be due to being associated with proteinuria, primary glomulonephritis, and poor graft function also GIT side effects too with the usual side effects.
They are of benefit in particular groups of patients as those with malignancies, encapsulating peritoneal sclerosis, BK and CMV virus infections.
Professor Ahmed Halawa
Admin
3 years ago
Thank you All
Mohamad Habli
3 years ago
• mTORi are class of drugs that inhibit the mechanistic target of rapamycin in the cytoplasm. m-TOR is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase related kinases.
• mTOR is implicated in the regulation of cellular metabolism, growth, and proliferation through two protein complexes signaling mTORC1 and mTORC2.
• Sirolimus is the first m-TORi. Rapamycin is a macrocyclic antibiotic that is produced by Streptomyces hygroscopicus.
• Sirolimus was originally developed as an antifungal agent, but the discovery of it’s IS effects led to it’s FDA approval in 2003 for prevention of acute allograft rejection.
Summary
-Use m-TORi in low immunological recipients. -Use m-TORi in patients with malignancy, encapsulating peritoneal sclerosis, CMV, and BK virus infections
-Do not use mTOR inhibitors routinely as part of an initial maintenance immunosuppression regimen in all patients.
-Sirolimus or Evirolimus can be used in combination with low dose CNI as maintenance therapy to minimize the side effects of CNI, potentiate IS and immunomodulation.
-mTOR inhibitor can be used alternatively in:
-Patients who cannot tolerate CNI due to nephro- or neurotoxicity
-Patients who develop cancer after transplantation
-Recipients who are noncompliant with therapy because of side effects
• When considering mTORi therapy , monitor levels, and check for side effects and adverse events.
Huda Al-Taee
3 years ago
mTOR inhibitors had been used in renal transplantation for over 2 decades.
They have been used in different IS medications protocols such as CNI free regimens, combination with low dose CNI. Their use was prefered in low immunological risk patients with GFR> 40 and no significant proteinuria, many studies reported comparable graft rejection and improved renal function as compared to CNI. mTOR inhibitors use in high risk patients is less studied with variable results. the use of mTORi is cost effective. their main use is in cases of malignancy, post transplant encapsulating peritoneal sclerosis, CMV, and BK infection. there is a drop in their use due to their side effect profile, in addition there is a concern about their link to increased mortality. most common side effects are: proteinuria, primary glomerulonephritis, GI symptoms associated with poor quality of life. more studies are needed to evaluate the long term efficacy and safety of mTORi in kidney transplantation.
Weam Elnazer
3 years ago
mTOR-I inhibitors have been used in kidney transplantation for almost two decades. They have been utilized in various immunosuppressive combinations for low-risk group renal transplantation. CNI-free protocols employ them either as a de novo regiment or as a conversion from CNIs. Many of these trials revealed lower graft rejection rates and higher eGFR than typical CNI regimens. Also, using mTOR-I with CNIs allowed for lower dosages of CNIs, reducing adverse effects and improving graft outcomes. They are particularly interested in renal transplant patients with malignancy, encapsulating peritoneal sclerosis, CMV, and BK virus infections. Moreover, mTOR-I treatments had equivalent outcomes to normal protocols among patients of extended-criteria kidney transplants. In high-risk renal transplantation, they have been tested sparingly, with mixed results. Their usage has been linked to many adverse outcomes, including increased mortality. Many of the trials known to date also showed substantial dropout rates. More research is required to address the issues raised.
Immunosuppressive treatments with mTOR-I had similar graft survival and improved eGFR than traditional procedures in low-risk renal transplants.
However, their efficacy in high-risk populations is unknown.
They are particularly useful in individuals with malignancies, encapsulating peritoneal sclerosis, and BK and CMV viral infections. They have unacceptably high adverse effects, resulting in significant discontinuation rates. These may have contributed to their current decline in popularity (both early and maintenance). A new worry links their usage to greater patient death. More research on mTOR-safety I’s is required.
Ban Mezher
3 years ago
Several studies show that mTOR-I can be used in low risk renal transplantation instead of CNI without increasing risk of rejection, and similar patient &graft outcome, with higher GFR, but its associated with high rate of discontinuation due to adverse effects ( >50%).
In high risk transplant, mTOR-I studies were limited, & the results showed no difference in graft out come when compared to CNI with high rate of side effects.
mTOR-I now used in selected recipients with CNI nephrotoxicity or recipients with history of malignancy as NMSC and PTLD.
Sherif Yusuf
3 years ago
mTOR inhibitors are ant proliferative drugs that inhibit the proliferation of T cells ,B cells, fibroblast, vascular smooth muscle and certain malignant cells
2 drugs are included in this family : everolimus and sirolimus, everolimus has better bioavailability than sirolimus
These drugs have narrow therapeutic range so monitoring of these drugs using a whole blood sample is mandatory
Also, they have drug-drug interactions as it is metabolized in the liver with CYTP450
The combination of cyclosporine (not tacrolimus) and m TOR inhibitors requires dose reductions of both drugs due to synergistic drug interaction that may cause nephrotoxicity
Several protocols using m TOR are existing
CNI avoidance regimen with denovo use of mTOR inhibitors (use of mTOR inhibitors form the start of transplantation), together with MMF and sterioids
CNI conversion regimen which may be early ( within 6 months of transplantation) or late (after 6 months of transplantation)
CNI minimization regimen in which m TOR inhibitors is combined with low dose CNI, one regimen is to use everolimus in a dose of 1.5 mg twice daily together with tacrolimus and maintaining trough level at 5-8 ng/ml for both drugs in first 2 months and then 3-5 ng/ml thereafter.
Benefit of using m TOR inhibitors
Reduction of the risk of malignancies including skin cancers since it is antiproliferative. One study found that drug Shift from CNI to sirolimus was associated with 40% reduction of malignancy including skin cancer
Lower risk of opportunistic k, CMV, and BK virus infections
Reduce the risk of CAN which was observed only in denovo and early conversion since there is no benefit was observed if damage to the kidney already happen with GFR< 30 or proteinuria > 1 gm
Better preservation of GFR
Problems associated with using m TOR inhibitors (toxic drugs with dose dependent toxicity)
Increase the risk of delayed wound healing, lymphocele, perioperative skin infection, and late incisional hernia if given from the start of transplantation
Increased risk of rejection
Increased risk of non-opportunistic infections
Nephrotoxicity including podocytopathy leading to proteinuria which is associated with poor graft survival or tubular injury leading to AKI.
Mouth ulcer
Dermatitis in hand or feet and sometimes vasculitic rash
Pneumonitis
Severe gastrointestinal symptoms
Hepatitis
Amenorrhea and testicular dysfunction
Sirolimus induced bone pair due to hyperemia and BM oeddma
BM supression
Increased risk of PTDM
Dyslipidemia as it increase no HDL cholesterol
Increase in cardiovascular risk
High discontinuation rate due to frequent side effects
Increase all-cause mortality
Sirolimus can be used only in low risk renal transplant patients as it is not studied well in high risk patients moreover limited studies suggest use in high risk transplant patient sis associated with higher rejection, lower graft survival and lower GFR
Different regimes used in low risk renal transplant recipients and its impact on graft survival
CNI avoidance showed inferior results as it increase in the risk of biopsy proven AR , and is associated with more complications.
Early conversion to sirolimus (within 6 months post transplantation) was found to decrease the risk of CAN (by some studies), better GFR but increase in the the risk of biopsy proven AR when compared to convintional regimen using tacrolimus, MMF, sterods
Late conversion to sirolimus was associated with increase in the rate of BPAR and no improvement of CAN.
CNI minimization regimen is associated with similar acute rejection rate , lower incidince of CMV infection, better eGFR and good graft survival with no increase in proteinuria when compared to convintional regimen using tacrolimus, MMF, sterods
Precautions when using m TOR inhibitors as a maintanace immunosuppression for transplant recipient
Use only in low immunologically risk patients, first transplant or second transplant with non immunological cause of graft loss
Either to treat or to avoid CNI related complications (malignancy, infection, CAN)
In African American bioavailability is lower so they may need higher doses with more toxic drug effect so it may not be suitable for this group of patients
If pregnancy anticipated this drug should be avoided
Not suitable for obese transplant recipient with BMI> 30
Conversion should not be done if GFR< 30 or proteinuria > 0.5-1 gm
Regimens that can be used
1. CNI minimization (no increase in the rate of rejection and decrease side effects of CNI including CAN, infection, malignancies)
2. Early conversion to prevent occurrence of CAN, have better GFR, and lower the risk of malignancy and infection but acute rejection rate may be increased so risk benefit ratio should be taken in consideration.
3. Late conversion the benefit from conversion at that time is low as conversion will not decrease the incidence of CAN and patients are usually maintained on lower doses of CNI at that time with lower incidence of malignancy and infection in these low risk patients, on the other hand conversion could be commenced only in the context of severe side effects of CNI such as Kaposi sarcoma.
Mujtaba Zuhair
3 years ago
The use of immunosuppressive drugs is important to prevent graft rejection . The most commonly used regimen including steroids ,CNI, and MMF. with this regimen , 1 year graft survival is improved. But the improvement in long term graft survival is still a major problem. One concern is about CNI nephropathy as a cause of late graft loss.
So many drugs is developed and incorporated in clinical trials to negate this effect.
mTOR inhibitors had been used in transplantation for many years and many trials had evaluated it’s effects. The summery of these trials that mTOR inhibitors use is associated with good graft survival and better eGFR in low risk transplantation but more trials is needed in high risk patients.
mTOR inhibitors is also an antifibrotic agent and had some antiviral activity and it’s use is associated with lower incidence of malignancies like non-melanoma skin cancer and post transplantation lymphoproliferative disorders.
Also mTOR use is associated with high rate of discontinuation due to high rate of serious side effects ( delayed graft function, proteinuria , mouth ulcers, poor wound healing, lymphocele , interstitial pneumonitis , hyperlipidemia) .
Due to these side effects , the use of mTOR is limited to limited number of conditions like in malignancies, BK virus and CMV virus infections, and sclerosing peritoneal sclerosis post transplantation.
Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation Role of mtor i in renal transplantation
1)CNI avoidance with De novo m TOR-I introduction
Larson et al. studied in a prospective randomized trial, comparing sirolimus, MMF and prednisolone to tacrolimus, MMF and prednisolone , for an average of 33 months. At one year, patients’ survival, graft survival, eGFR and acute rejection were similar in the two groups.
2)Conversion from CNI into mTOR-I at a later stage
In the CONCEPT trial (2009), 192 patients who were on dacluzimab induction, and baseline CyA, MMF and prednisolone (which was withdrawn at 8 months), were studied prospectively. At 3 months post transplantation 95 were randomized to convert to sirolimus and 97 remained on CyA. Patient survival was similar and there was improved eGFR on the sirolimus group. However, the sirolimus group showed non-signifcantly more acute rejection (17% vs. 8%), and signifcantly more hyperlipidemia, lower HB, and more proteinuria.
Spare-the nephron trial (2011) 299 patients who were on initial CNI/MMF protocols were randomized afer 30 to 180 days into MMF/ sirolimus (148 patients) and MMF/CNI (151 patients). Patients induction therapy including thymoglobulin, basiliximab, dacluzimab and Muromonab-CD3. At 24 months, patients who were on sirolimus/MMF had signifcantly higher eGFR compared to those on CyA/MMF. Also the eGFR was nonsignifcantly higher among patients who were on sirolimus/MMF compared to tacrolimus/MMF. Patients on the sirolimus/MMF has similar opportunistic infection to the CNI/MMF group, however, they had signifcantly more dyslipidaemia, oedema, proteinuria and mouth ulcers.
In the ORION study (2011), Flechner et al. studied 3 treatment groups: sirolimus plus tacrolimus (tacrolimus withdrawal afer 13 months, n=152 patients), sirolimus plus MMF (n=152 patients) and tacrolimus+MMF (139 patients). There was more biopsy-proven rejection among the sirolimus/MMF group leading to discontinuation of that arm. There was more rejection in the sirolimus group; however,graft survival was similar in the remaining two groups.
SCORATES study, 126 patients on CyA, MMF, steroids and basiliximab for induction were randomized 14 days after transplantation into three groups to eliminate MMF plus either CNI or steroids. Group 1 (n=45): The CNI withdrawal group (CNI-WD), CNI plus MMF were withdrawn and continued on everolimus plus steroids; group 2 (n=40): The steroid withdrawal group (steroid-WD) in which MMF and steroids were withdrawn, and they continued on everolimus plus CNI; and group 3 (n=22): The control group with CNI, MMF and steroids. The steroid-WD was discontinued prematurely as there was high rate of discontinuation. At 12 months, in the everolimus group, the eGFR was non-inferior; however there was significantly more rejection and a trend towards more graft and patient loss.
ELITE Symphony study (2007), 1645 patients were treated with standard CyA, MMF and steroids; low dose tacrolimus with dacluzimab in the frst 2 months; low dose CyA and MMF; and low dose sirolimus with dacluzimab for two months. Te patients were followed for one year: the low dose tacrolimus showed significantly higher eGFR, less rejection and better graft survival compared to all
other group.
3) mTOR-I was used in combination with CNI as CNI sparing regiments
Oh et al. studied 148 renal transplant recipients for 1 year. Patients were randomized one month after transplantation to receive everolimus, low dose CyA or to have MMF plus standard CyA dose.
AR rate were similar in the two groups, but there was significantly higher eGFR among the everolimus group.
High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols.
Uchida et al. studied 16 stable ABO incompatible renal transplant recipients who were on MMF and standard CNI. MMF was substituted by everolimus with low dose CNI, and there was no increased rejection at three months.
Lee et al. reported an unfavourable outcome in a pilot study of 28 sirolimus-based high-risk renal transplant recipient compared to 69 control patients on MMF, CNI and prednisolone.
A recent systematic review and meta-analysis of 21 RCT studies included 5876 patients, was conducted by Knoll et al. It was demonstrated that mTOR-I use, although associated with a 40% reduction of malignancy and 56% reduction of non-melanoma skin cancer, was associated with an increased risk of mortality.
Immunosuppressive protocols containing mTOR-I are generally efective in low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols. Limited efficacy in high-risk groups. They are of particular interest in patients having malignancies, encapsulating peritoneal sclerosis, BK and CMV virus infections.
m-TOR-I are immunosuppressive drugs inhabiting signal 3 of lymphocyte proliferation ,members of this group are:everolimus and sirolinus
Immunosuppressive protocols containing mTOR-I are generally effective in :
1)-low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols. However, we have limited reports on their efficacy in high-risk groups.
2)-malignancies,
3)-encapsulating peritoneal sclerosis
4)- BK
5)- CMV virus infections.
They were shown to have unacceptable side effect profile leading to high discontinuation rate. E.g priteinuria ,hyperlipidemia These might have contributed to their reduced popularity (both as early and maintenance) in the recent years. Moreover there is a new concern linking their use to increased patients’ mortality. More studies, looking into the safety of mTOR-I, are needed.
mTOR inhibitors like everolimus and sirolimus is mammalian target of rapamycin act on signal 3 inhibtion of T-Cell activation its used mainly as maintenance immunosuppressive therapy since the last two decades mainly in low immunological risk as CNI sparing agent or early CNI conversion , de-novo use or CNI minimization protocols in many studies with comparable results in regards of graft and patient survival and better renal function compared to CNI protocol but as per systematic review and meta-analysis studies confirmed that the use of mTOR inhibitors with CNI minimization or elimination associated with higher BPAR rate without effect on mortality or graft or patient survival rate with better glomerular filtration rate compared to CNI based protocol , recent prospective trails comparing the use of m TOR PLUS MMF combination compared to CNI tacrolimus plus MMF protocol which conclude both are effective with similar graft and patient survival .
few studies address the efficacy of MTOR I in high immunological risk recipients and recipients with ECD with short follow up of 12 months in most of the studies which shows comparable results to CNI based IS but more side effects with the use of mTOR I Like myelosuppression ,mouth ulcerations metabolic effect with hypertriglyceridemia and hyperlipidemia , protineuria with infections like wound infection , CMV , POST transplant Peritoneal sclerosing fibrosis , Interstitial pnemonitis
still its preferred immunosuppressive agent in specific group of kidney transplant patients like those with malignancy, BK, cmv infections
still, we need more large studies to assess the long-term efficacy of the m TORI in the kidney transplant field.
mTMORI was introduced to the field of transplantation over the 20 years. Its has been used mainly in low risk patients under different therapeutic strategies. The ideal candidates for mTORI are ; a) low immunologic risk, b) malignancies, c) encapsulating peritoneal fibrosis, d) BKV nephropathy, e) CMV infections. The protocols for using for using mTORI includes ; CNI avoidance, CNI minimization , and CNI withdrawal. The mechanism of action is through inhibition of signal-3 of T cell activation.. Several studies demonstrated comparable allograft rejection rejection rate, and better renal function in comparison t o standard CNI protocols. The use of mTORI allowed minimal doses of CNI which is beneficial in decreasing side effect of CNI without jeopardising allograft function. mTORI has been tried as well in high risk in small scale with mixed results. Although mTORI is associated with 40% decrease in malignancy and 56% decrease in non-melanoma skin cancer, there is a recent concern about risk of mortality(105). The drug was discontinued in up to 53.2% due to proteinuria, primary glomerulonephritis, and poor graft function(106). Another problem is GI side effects which significantly associated with poor quality of life(107). Regarding the cost of treatment, some studies showed low cost for sirolimus treated group(104). Currently small numbers of patients are on mTORI(low risk) compared to larger numbers on CNI specially tacrolimus. Most of the studies addressing the mTORI are short studies, there studies are needed to evaluate the long-term effect on the drug over long run.
Use of mTORi have been studied by many researchers to replace CNIs and to minimize the chronic nephrotoxicity of CNIs.
mTOR-I used in kidney transplant for longtime.
They have been used in different combination immunosuppressant for low risk group
renal transplantation.
used in the various state:
CNI-free protocols: either as De novo regiments, or by conversion from CNIs at a later
stage.
Many studies reported comparable graft rejection rate and a better kidney function
compared to standard CNI protocols.
mTOR-I when used in combination with CNIs:
Facilitated the use of lower doses of CNIs with the resultant reduction of CNI related
side effects, without seriously compromising graft outcome.
Certain group of renal transplant recipients:
Malignancy.
Post-transplant encapsulating peritoneal sclerosis.
CMV and BK virus infections.
Recipients of kidneys from extended-criteria transplantation.
However, only few reports studied their use in high risk group renal transplantation, with
variable outcomes.
A drop in their popularity in the recent years, and their use was associated with multiple
adverse events, in addition to a recent concern of their link to increased mortality.
Also, a high discontinuation rate was demonstrated across many of the studies available
to date.
In this comprehensive review thoroughly summarized the mTOR-I’s, one can conclude that the backbone of the immune suppression in renal transplant patients is CNIs (primarily Tacrolimus). mTOR inhibitors were found effective, non-inferior, etc when the replaced MMF not CNIs in most of the studies. except for some indications like malignancy and intractable side effects of CNIs mTOR inhibitors are very helpful in maintaining the immune suppression and prevention of acute rejection.
mTOR inhibitors inhibit T&B cells ,fibroblasts, vascular smooth muscles and some malignant cells. They include everolimus (better bioavailability) and everolimus. Their level monitoring is mandatory as they have narrow therapeutic range .There are also several drug-drug interactions with hepatic metabolism with CYTP450.Due to synergistic drug-drug interaction with cyclosporine ,dose reduction of both drugs is needed in case of concomitant use. Based on this, several protocols were adopted including CNI avoidance, minimization and conversion; either early or late.
Beneficial effects of mTOR
.Antiproliferative effect decrease risk of malignancy including skin cancers
.Less risk of opportunistic infections
.Better GFR and decreased risk of CAN.
Adverse effects
Delayed wound healing, increased risk of rejection ,non opportunistic infection ,podocytopathy ,hepatitis mouth ulcers ,pneumonitis, bone marrow suppression, PTDM ,and increase all-cause mortality among others.
mTOR inhibitors have place in low risk with advantage of better GFR than conventional protocols .Also ,they have advantage in certain situations including malignancies, encapsulating peritoneal sclerosis, BK and CMV viral infections. However ,their use is limited by side effects and possible increased mortality.
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
Mammalian target of rapamaycin inhibitors (mTOR-I) has been in use in kidney transplantation in different combination with immunosuppressant for low risk group mTOR binds to FK protein but would not inhibit calcineurin. Their complex with calcineurin binds to rapamycin target and inhibit signal 3 of T-cell activation, through inhibition of cytokines activating T-cell cycle .
CNI-free protocols, either as De novo regiments, or by conversion from CNIs at a later stage.
– combination with CNIs, result in reduction of CNI related side effects, without affecting the graft outcome.
– Patient with certain conditions like malignancy, post-transplant encapsulating peritoneal scelorosis, CMV and BK virus infections.
– protocols containing mTOR-I showed comparable results to standard protocols among recipients of kidneys from extended-criteria transplantation.
-Their use in high risk group renal transplantation is reported to be associated with variable outcomes.
Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation;
Immunosuppressive protocols containing mTOR-I are generally effective in low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols.
High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols;
Immunosuppressive protocols containing mTOR-I have limited reports on their efficacy in high-risk groups with variable outcome .
Safety of mTOR-I Protocols in Kidney Transplantation;
Side effects include, GI symptoms , poor wound healing , hyperlipidaemia and worsening proteinuria . Using mTOR cause reduction of malignancy {non-melanoma skin cancer } .
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
The mTOR-I ( sirolimus and evarolimus) binds to FK protein inhibiting signal 3 of T-cell activation.
Use of mTOR-I Among Low/ standard Risk Renal Transplantation:
· In CNI avoidance with De novo m TOR-I introduction
· Conversion from CNI into mTOR-I preserve eGFR and help to spare CNI with good graft survival and variable rejection rate .
· In CNI avoiding regimen sirolimus showed similar result to CNI based regimen at one year, regarding patients’ survival, graft survival, eGFR and acute rejection .
Sirolimus cause more dyslipidaemia, oedema, proteinuria and mouth ulcer.
Using mtor with CNI elimination have significantly more rejection, without increasing patient mortality or graft loss, and a better eGFR compared to the standard CNI protocols while with CNI minimization ,there are similar graft rejection compared to the standard CNI protocols .
High-Risk Renal Transplantation & Extended-Criteria
Few studies are available. Sirolimus was comparable to azathioprin in cyclosporine based regimen and with MMF in CNI based regimen. Other studies contradict this but the difference was non-significant
The cost of treatment
The cost of treatment and graft loss were compared among 4 groups: early sirolimus+ withdrawal of
steroids/CNI, early transition by sirolimus, early transition by everolimus, and the standard prednisolone, MMF and CNI. The lowest cost was for early sirolimus transition group .
Safety of mTOR-I Protocols in Kidney Transplantation
Using mTOR cause 40% reduction of malignancy and 56% reduction of non-melanoma skin cancer, but there is high risk of mortality and adverse reactions leading to discontinuation of their use reaching to 53.2%. These reactions included Proteinuria, primary glomulonephritis, poor graft function and GIT discofort.
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
mTOR inhibitors: The mammalian target of rapamycin (mTOR) inhibitors are immunosuppressants sirolimus and everolimus which inhibit T cell proliferation. These drugs, in addition to their effect on immune system, also have anticancer properties, antiviral action (against BK virus and CMV) as well as cardiovascular protective effects like inhibition of intimal proliferation and action on atherosclerotic plaque. Due to the nephrotoxic action of calcineurin inhibitors (CNI), mTOR inhibitors have been used in kidney transplantation.
Different mTOR inhibitor based protocols: mTOR inhibitors have been used both as de novo as well as conversion to CNIs or addition to CNI based regimen with CNI minimization.
A) 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%
B) mTOR inhibitor based CNI minimization: mTOR inhibitor based CNI minimization led to non-inferior results but increased adverse events leading to increased rates of discontinuation of mTOR inhibitors.
C) CNI conversion: Changing CNI with 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.
Role of mTOR inhibitors in transplantation: Considering the results of these studies, it is advisable to continue a CNI (especially tacrolimus), MMF and steroid based regime for 3 to 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, no DSA), completely healed wound, no risk of recurrence (basic disease causing ESRD is not glomerulonephritis) and well-tolerating antiproliferative agents, then CNI can be replaced with mTOR inhibitor.
What is the current of MTOR inhibitor in kidney transplantation
mTOR-I, comprised of sirolimus and evarolimus, binds to FK protein but would not inhibit calcineurin. Their complex with calcineurin binds to rapamycin target and inhibit signal 3 of T-cell activation, through inhibition of cytokines activating T-cell cycle .
mTOR-inhibitor have been used in the following ;
– In different combination immunosuppressant for low risk group renal transplantation.
– In various CNI-free protocols, either as De novo regiments, or by conversion from CNIs at a later stage.
– In combination with CNIs, facilitated the use of lower doses of CNIs with the resultant reduction of CNI related side effects, without seriously compromising graft outcome.
– In certain group of renal transplant recipients, including those with malignancy, post-transplant encapsulating peritoneal scelorosis, CMV and BK virus infections.
– protocols containing mTOR-I showed comparable results to standard protocols among recipients of kidneys from extended-criteria transplantation.
-Their use in high risk group renal transplantation is reported to be associated with variable outcomes.
Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation;
Immunosuppressive protocols containing mTOR-I are generally effective in low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols.
High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols;
Immunosuppressive protocols containing mTOR-I have limited reports on their efficacy in high-risk groups.
Safety of mTOR-I Protocols in Kidney Transplantation;
Immunosuppressive protocols containing mTOR-I have unacceptable side effect profile leading to high discontinuation rate and these including infection , GI symptoms , poor wound healing , hyperlipidaemia, deceased sperm count in males on sirolimus and worsening proteinuria . Moreover there is a new concern linking their use to increased patients’ mortality.
.
What is the current position of m-TOR Inhibitors in Kidney Transplantation?
Maintenance immunosupressive treatment includes mTOR-I, consisting of sirolimus and evarolimus,
Its mode of action is by binding to FK protein then make complex with calcineurin which binds to rapamycin target and inhibit signal 3 of T-cell activation, .
It’s advantage is that it can lead to reduction of malignancy, mainly non-melanoma skin cancer and accompanied with lesser CMV viremia , and had positive effect in BK viremia/BK associated nephropathy and post-transplant encapsulating peritoneal sclerosis, on the other hand studies mentioned that it was associated with an increased risk of mortality.
Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation
Some studies assessed CNI avoidance with De novo m TOR-I introduction, or shifting from CNI into mTOR-I .
mTor I with low dose CNI showed good graft survival and low rejection rate
Everolimus with CNI elimination led to increased rejection risk , without increasing patient mortality or graft loss, and a better eGFR.
when mTOR-I replaced CNI , the rejection rate was similar, lower creatinine and more marrow suppression; when substituted antimetabolites there was less rejection and lower CMV infection but higher hyperlipidaemia.
mTOR-I combination with CNI graft and patient survival were similar in different immunosuppressive strategies .
Patients on low dose mTOR-I had more rejection and better eGFR compared to the high dose with similar CNI doses.
High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols
mTOR-I is as good as other standard protocols among recipients of extended-criteria donors.
MMF was substituted by everolimus with low dose CNI, and there was no increased rejection at three months in a study.
mTOR-I showed acceptable results among high immunologic risk cases.
Withdrawal of mTOR-I could be due to being associated with proteinuria, primary glomulonephritis, and poor graft function also GIT side effects too with the usual side effects.
They are of benefit in particular groups of patients as those with malignancies, encapsulating peritoneal sclerosis, BK and CMV virus infections.
Thank you All
• mTORi are class of drugs that inhibit the mechanistic target of rapamycin in the cytoplasm. m-TOR is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase related kinases.
• mTOR is implicated in the regulation of cellular metabolism, growth, and proliferation through two protein complexes signaling mTORC1 and mTORC2.
• Sirolimus is the first m-TORi. Rapamycin is a macrocyclic antibiotic that is produced by Streptomyces hygroscopicus.
• Sirolimus was originally developed as an antifungal agent, but the discovery of it’s IS effects led to it’s FDA approval in 2003 for prevention of acute allograft rejection.
Summary
-Use m-TORi in low immunological recipients.
-Use m-TORi in patients with malignancy, encapsulating peritoneal sclerosis, CMV, and BK virus infections
-Do not use mTOR inhibitors routinely as part of an initial maintenance immunosuppression regimen in all patients.
-Sirolimus or Evirolimus can be used in combination with low dose CNI as maintenance therapy to minimize the side effects of CNI, potentiate IS and immunomodulation.
-mTOR inhibitor can be used alternatively in:
-Patients who cannot tolerate CNI due to nephro- or neurotoxicity
-Patients who develop cancer after transplantation
-Recipients who are noncompliant with therapy because of side effects
• When considering mTORi therapy , monitor levels, and check for side effects and adverse events.
mTOR inhibitors had been used in renal transplantation for over 2 decades.
They have been used in different IS medications protocols such as CNI free regimens, combination with low dose CNI. Their use was prefered in low immunological risk patients with GFR> 40 and no significant proteinuria, many studies reported comparable graft rejection and improved renal function as compared to CNI. mTOR inhibitors use in high risk patients is less studied with variable results. the use of mTORi is cost effective. their main use is in cases of malignancy, post transplant encapsulating peritoneal sclerosis, CMV, and BK infection. there is a drop in their use due to their side effect profile, in addition there is a concern about their link to increased mortality. most common side effects are: proteinuria, primary glomerulonephritis, GI symptoms associated with poor quality of life. more studies are needed to evaluate the long term efficacy and safety of mTORi in kidney transplantation.
mTOR-I inhibitors have been used in kidney transplantation for almost two decades. They have been utilized in various immunosuppressive combinations for low-risk group renal transplantation. CNI-free protocols employ them either as a de novo regiment or as a conversion from CNIs. Many of these trials revealed lower graft rejection rates and higher eGFR than typical CNI regimens. Also, using mTOR-I with CNIs allowed for lower dosages of CNIs, reducing adverse effects and improving graft outcomes. They are particularly interested in renal transplant patients with malignancy, encapsulating peritoneal sclerosis, CMV, and BK virus infections. Moreover, mTOR-I treatments had equivalent outcomes to normal protocols among patients of extended-criteria kidney transplants. In high-risk renal transplantation, they have been tested sparingly, with mixed results. Their usage has been linked to many adverse outcomes, including increased mortality. Many of the trials known to date also showed substantial dropout rates. More research is required to address the issues raised.
Immunosuppressive treatments with mTOR-I had similar graft survival and improved eGFR than traditional procedures in low-risk renal transplants.
However, their efficacy in high-risk populations is unknown.
They are particularly useful in individuals with malignancies, encapsulating peritoneal sclerosis, and BK and CMV viral infections. They have unacceptably high adverse effects, resulting in significant discontinuation rates. These may have contributed to their current decline in popularity (both early and maintenance). A new worry links their usage to greater patient death. More research on mTOR-safety I’s is required.
Several studies show that mTOR-I can be used in low risk renal transplantation instead of CNI without increasing risk of rejection, and similar patient &graft outcome, with higher GFR, but its associated with high rate of discontinuation due to adverse effects ( >50%).
In high risk transplant, mTOR-I studies were limited, & the results showed no difference in graft out come when compared to CNI with high rate of side effects.
mTOR-I now used in selected recipients with CNI nephrotoxicity or recipients with history of malignancy as NMSC and PTLD.
mTOR inhibitors are ant proliferative drugs that inhibit the proliferation of T cells ,B cells, fibroblast, vascular smooth muscle and certain malignant cells
2 drugs are included in this family : everolimus and sirolimus, everolimus has better bioavailability than sirolimus
These drugs have narrow therapeutic range so monitoring of these drugs using a whole blood sample is mandatory
Also, they have drug-drug interactions as it is metabolized in the liver with CYTP450
The combination of cyclosporine (not tacrolimus) and m TOR inhibitors requires dose reductions of both drugs due to synergistic drug interaction that may cause nephrotoxicity
Several protocols using m TOR are existing
Benefit of using m TOR inhibitors
Problems associated with using m TOR inhibitors (toxic drugs with dose dependent toxicity)
Sirolimus can be used only in low risk renal transplant patients as it is not studied well in high risk patients moreover limited studies suggest use in high risk transplant patient sis associated with higher rejection, lower graft survival and lower GFR
Different regimes used in low risk renal transplant recipients and its impact on graft survival
Precautions when using m TOR inhibitors as a maintanace immunosuppression for transplant recipient
Regimens that can be used
1. CNI minimization (no increase in the rate of rejection and decrease side effects of CNI including CAN, infection, malignancies)
2. Early conversion to prevent occurrence of CAN, have better GFR, and lower the risk of malignancy and infection but acute rejection rate may be increased so risk benefit ratio should be taken in consideration.
3. Late conversion the benefit from conversion at that time is low as conversion will not decrease the incidence of CAN and patients are usually maintained on lower doses of CNI at that time with lower incidence of malignancy and infection in these low risk patients, on the other hand conversion could be commenced only in the context of severe side effects of CNI such as Kaposi sarcoma.
The use of immunosuppressive drugs is important to prevent graft rejection . The most commonly used regimen including steroids ,CNI, and MMF. with this regimen , 1 year graft survival is improved. But the improvement in long term graft survival is still a major problem. One concern is about CNI nephropathy as a cause of late graft loss.
So many drugs is developed and incorporated in clinical trials to negate this effect.
mTOR inhibitors had been used in transplantation for many years and many trials had evaluated it’s effects. The summery of these trials that mTOR inhibitors use is associated with good graft survival and better eGFR in low risk transplantation but more trials is needed in high risk patients.
mTOR inhibitors is also an antifibrotic agent and had some antiviral activity and it’s use is associated with lower incidence of malignancies like non-melanoma skin cancer and post transplantation lymphoproliferative disorders.
Also mTOR use is associated with high rate of discontinuation due to high rate of serious side effects ( delayed graft function, proteinuria , mouth ulcers, poor wound healing, lymphocele , interstitial pneumonitis , hyperlipidemia) .
Due to these side effects , the use of mTOR is limited to limited number of conditions like in malignancies, BK virus and CMV virus infections, and sclerosing peritoneal sclerosis post transplantation.
Immunosuppressive Protocols Using mTOR-I Among Low Risk Renal Transplantation
Role of mtor i in renal transplantation
1)CNI avoidance with De novo m TOR-I introduction
Larson et al. studied in a prospective randomized trial, comparing sirolimus, MMF and prednisolone to tacrolimus, MMF and prednisolone , for an average of 33 months. At one year, patients’ survival, graft survival, eGFR and acute rejection were similar in the two groups.
2)Conversion from CNI into mTOR-I at a later stage
In the CONCEPT trial (2009), 192 patients who were on dacluzimab induction, and baseline CyA, MMF and prednisolone (which was withdrawn at 8 months), were studied prospectively. At 3 months post transplantation 95 were randomized to convert to sirolimus and 97 remained on CyA. Patient survival was similar and there was improved eGFR on the sirolimus group. However, the sirolimus group showed non-signifcantly more acute rejection (17% vs. 8%), and signifcantly more hyperlipidemia, lower HB, and more proteinuria.
Spare-the nephron trial (2011) 299 patients who were on initial CNI/MMF protocols were randomized afer 30 to 180 days into MMF/ sirolimus (148 patients) and MMF/CNI (151 patients). Patients induction therapy including thymoglobulin, basiliximab, dacluzimab and Muromonab-CD3. At 24 months, patients who were on sirolimus/MMF had signifcantly higher eGFR compared to those on CyA/MMF. Also the eGFR was nonsignifcantly higher among patients who were on sirolimus/MMF compared to tacrolimus/MMF. Patients on the sirolimus/MMF has similar opportunistic infection to the CNI/MMF group, however, they had signifcantly more dyslipidaemia, oedema, proteinuria and mouth ulcers.
In the ORION study (2011), Flechner et al. studied 3 treatment groups: sirolimus plus tacrolimus (tacrolimus withdrawal afer 13 months, n=152 patients), sirolimus plus MMF (n=152 patients) and tacrolimus+MMF (139 patients). There was more biopsy-proven rejection among the sirolimus/MMF group leading to discontinuation of that arm. There was more rejection in the sirolimus group; however,graft survival was similar in the remaining two groups.
SCORATES study, 126 patients on CyA, MMF, steroids and basiliximab for induction were randomized 14 days after transplantation into three groups to eliminate MMF plus either CNI or steroids. Group 1 (n=45): The CNI withdrawal group (CNI-WD), CNI plus MMF were withdrawn and continued on everolimus plus steroids; group 2 (n=40): The steroid withdrawal group (steroid-WD) in which MMF and steroids were withdrawn, and they continued on everolimus plus CNI; and group 3 (n=22): The control group with CNI, MMF and steroids. The steroid-WD was discontinued prematurely as there was high rate of discontinuation. At 12 months, in the everolimus group, the eGFR was non-inferior; however there was significantly more rejection and a trend towards more graft and patient loss.
ELITE Symphony study (2007), 1645 patients were treated with standard CyA, MMF and steroids; low dose tacrolimus with dacluzimab in the frst 2 months; low dose CyA and MMF; and low dose sirolimus with dacluzimab for two months. Te patients were followed for one year: the low dose tacrolimus showed significantly higher eGFR, less rejection and better graft survival compared to all
other group.
3) mTOR-I was used in combination with CNI as CNI sparing regiments
Oh et al. studied 148 renal transplant recipients for 1 year. Patients were randomized one month after transplantation to receive everolimus, low dose CyA or to have MMF plus standard CyA dose.
AR rate were similar in the two groups, but there was significantly higher eGFR among the everolimus group.
High-Risk Renal Transplantation & Extended-Criteria Renal Transplants and mTOR-I Protocols.
Uchida et al. studied 16 stable ABO incompatible renal transplant recipients who were on MMF and standard CNI. MMF was substituted by everolimus with low dose CNI, and there was no increased rejection at three months.
Lee et al. reported an unfavourable outcome in a pilot study of 28 sirolimus-based high-risk renal transplant recipient compared to 69 control patients on MMF, CNI and prednisolone.
A recent systematic review and meta-analysis of 21 RCT studies included 5876 patients, was conducted by Knoll et al. It was demonstrated that mTOR-I use, although associated with a 40% reduction of malignancy and 56% reduction of non-melanoma skin cancer, was associated with an increased risk of mortality.
Immunosuppressive protocols containing mTOR-I are generally efective in low risk renal transplantation, with a comparable graft survival and a better eGFR, compared to conventional protocols.
Limited efficacy in high-risk groups.
They are of particular interest in patients having malignancies, encapsulating peritoneal sclerosis, BK and CMV virus infections.