Timing of Sirolimus Initiation
Timing of Sirolimus Initiation
Given the reported increased risk of wound-healing problems, especially lymphocele development associated with sirolimus (SRL) treatment, what would you consider the earliest "safe" time interval to start SRL after transplantation?
I would like to add SRL (and reduce or even discontinue tacrolimus [TAC]) in a teenage patient who developed insulin-dependent diabetes mellitus immediately after transplantation (now postoperative day 16), associated with TAC and prednisone, which has not improved despite rapid prednisone taper. Because the patient has cystinosis, which by itself is associated with a high risk of eventual endocrine pancreas insufficiency, decreasing TAC and adding SRL may not be effective. Therefore, I certainly do not wish to complicate the course with a lymphocele. Even if not applicable to this case, I am curious to know your opinion regarding the timing of SRL initiation.
Martin Bitzan, MD
I believe that SRL can be started safely at any time after transplantation, since a number of centers use it as primary therapy. From a purely surgical standpoint, I would prefer to wait 4-6 weeks post transplantation to permit wound healing, minimize the risk of lymphocele development, and prevent thrombosis.
From an efficacy standpoint, if you are planning to switch your patient from a calcineurin inhibitor (CNI), such as TAC withdrawal, to SRL-based therapy, I would prefer to wait 3 months because the highest-risk period for acute rejection is from 3 weeks to 3 months after transplantation. In addition, I would use a daclizumab bridge at the time of SRL conversion (2 mg/kg daclizumab and repeat in 2 weeks) in order to provide suppression of the interleukin-2 pathway during the period of conversion because your patient is at high immunologic risk, being a teenager.
If you are planning to use SRL in combination with lower-dose TAC, particularly for posttransplant diabetes mellitus (PTDM) in a teenager, I would add SRL now (8-10 mg loading dose, then 3 mg/day and check levels) and lower TAC by 50% and monitor closely. I would target SRL levels of 10-12 ng/mL and TAC levels of 4-6 ng/mL. I would try to maintain the patient on TAC for at least 3 months post transplantation unless you believe that the toxicity (PTDM) outweighs the immunological benefit. You could probably provide adequate immunosuppression with SRL, mycophenolate mofetil, and either periodic doses of daclizumab or a single dose of alemtuzumab (30 mg) if you are concerned about breakthrough rejection.
At present, when we start SRL, we make sure that the patient is on pneumocystis prophylaxis (sulfamethoxazole and trimethoprim [Bactrim] SS daily or DS every Monday, Wednesday, and Friday); we check a lipid panel and repeat monthly and have a low threshold for starting atorvastatin; we check an iron profile and have a low threshold for starting erythropoietin alfa if the patient develops anemia (particularly on sirolimus + tacrolimus); and check a urine protein/creatinine ratio and repeat monthly and consider placing the patient on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker if proteinuria develops after CNI withdrawal.
Starting SRL at this point in time (16 days posttransplantation) is unlikely to cause a significant problem with lymphocele formation or wound healing, but I would be concerned with the level of maintenance immunosuppression if you are planning to stop TAC.
Given the reported increased risk of wound-healing problems, especially lymphocele development associated with sirolimus (SRL) treatment, what would you consider the earliest "safe" time interval to start SRL after transplantation?
I would like to add SRL (and reduce or even discontinue tacrolimus [TAC]) in a teenage patient who developed insulin-dependent diabetes mellitus immediately after transplantation (now postoperative day 16), associated with TAC and prednisone, which has not improved despite rapid prednisone taper. Because the patient has cystinosis, which by itself is associated with a high risk of eventual endocrine pancreas insufficiency, decreasing TAC and adding SRL may not be effective. Therefore, I certainly do not wish to complicate the course with a lymphocele. Even if not applicable to this case, I am curious to know your opinion regarding the timing of SRL initiation.
Martin Bitzan, MD
I believe that SRL can be started safely at any time after transplantation, since a number of centers use it as primary therapy. From a purely surgical standpoint, I would prefer to wait 4-6 weeks post transplantation to permit wound healing, minimize the risk of lymphocele development, and prevent thrombosis.
From an efficacy standpoint, if you are planning to switch your patient from a calcineurin inhibitor (CNI), such as TAC withdrawal, to SRL-based therapy, I would prefer to wait 3 months because the highest-risk period for acute rejection is from 3 weeks to 3 months after transplantation. In addition, I would use a daclizumab bridge at the time of SRL conversion (2 mg/kg daclizumab and repeat in 2 weeks) in order to provide suppression of the interleukin-2 pathway during the period of conversion because your patient is at high immunologic risk, being a teenager.
If you are planning to use SRL in combination with lower-dose TAC, particularly for posttransplant diabetes mellitus (PTDM) in a teenager, I would add SRL now (8-10 mg loading dose, then 3 mg/day and check levels) and lower TAC by 50% and monitor closely. I would target SRL levels of 10-12 ng/mL and TAC levels of 4-6 ng/mL. I would try to maintain the patient on TAC for at least 3 months post transplantation unless you believe that the toxicity (PTDM) outweighs the immunological benefit. You could probably provide adequate immunosuppression with SRL, mycophenolate mofetil, and either periodic doses of daclizumab or a single dose of alemtuzumab (30 mg) if you are concerned about breakthrough rejection.
At present, when we start SRL, we make sure that the patient is on pneumocystis prophylaxis (sulfamethoxazole and trimethoprim [Bactrim] SS daily or DS every Monday, Wednesday, and Friday); we check a lipid panel and repeat monthly and have a low threshold for starting atorvastatin; we check an iron profile and have a low threshold for starting erythropoietin alfa if the patient develops anemia (particularly on sirolimus + tacrolimus); and check a urine protein/creatinine ratio and repeat monthly and consider placing the patient on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker if proteinuria develops after CNI withdrawal.
Starting SRL at this point in time (16 days posttransplantation) is unlikely to cause a significant problem with lymphocele formation or wound healing, but I would be concerned with the level of maintenance immunosuppression if you are planning to stop TAC.
Source...