- Email: [email protected]
Initial experience using rapamycin immunosuppression in pediatric intestinal transplant recipients
IMMUNOSUPPRESSIVE REGIMENS
Initial Experience Using Rapamycin Immunosuppression in Pediatric Intestinal Transplant Recipients S. Horslen, C. Torres, D. Collier, K. Iyer, D. Sudan, B. Shaw, and A. Langas
R
APAMYCIN is a macrocyclic lactone immunosuppressant that is substantially free from nephrotoxic side effects. We present our preliminary experience with the use of rapamycin (sirolimus) in children following intestinal transplantation. Standard immunosuppression for small bowel transplantation at our center is a combination of tacrolimus and steroids. Renal dysfunction is the most frequent drug-related problem with standard tacrolimusbased immunosuppression. In the immediate postoperative period, tacrolimus levels are maintained in the 20- to 25-ng/mL range. RESULTS AND METHODS Sirolimus was introduced in 16 pediatric intestinal transplant patients (8 females, age range 1.3 to 19 years) in an attempt to spare the effects of calcineurin inhibitors on renal function. Twelve patients underwent combined liver and bowel transplantation, and four had isolated intestinal transplantation. Sirolimus was introduced between 13 days and 4.5 years after transplantation. The initial loading dose of sirolimus was 2 to 3 mg/m2 followed by 1 mg/m2 once per day and adjusted to achieve blood levels in the 8to 10-ng/mL range. Some of the children required sirolimus twice daily to achieve these levels, which differs from the adult data, which suggests that a once-daily dose is sufficient. As a general rule, the tacrolimus dose was decreased by 50% and adjusted according to blood levels, depending on the individual patient’s immunosuppressive requirements. The indications for the introduction of sirolimus therapy were nephrotoxicity in 14 patients, 1 for recurrent rejection, and 1 for acute rejection followed by persistent diarrhea. The child who received the drug for recurrent rejection also developed nephropathy in the form of nephrotic nephritic syndrome some months later, and this was believed to be related to the continued high levels of tacrolimus. Nephropathy in the other 14 patients was 0041-1345/02/$–see front matter PII S0041-1345(02)02677-5 934
manifested by hypertension and elevated creatinine in 12 patients. Two patients had evidence of pretransplant renal dysfunction. Two additional patients developed nephrotic nephritic syndrome, one of whom had evidence of pretransplant renal dysfunction. All 3 patients with nephritis underwent renal biopsy. The histology showed focal segmental glomerular sclerosis and thrombotic microangiopathy.
RESULTS
Of the 15 patients who had evidence of nephrotoxicity, 11 improved; 2 developed neutropenia immediately after starting on sirolimus, forcing its discontinuation before an effect could be seen; and 2 patients did not improve. Of the 2 not improving, one went on to receive a kidney transplant (this child had preexisting renal dysfunction and developed glomerular sclerosis), and the other patient died of early septic complications. Improvement in renal function was documented by better control of hypertension and reduced creatinine levels. Median creatinine level for this group before sirolimus therapy was 1.5 mg/dL and, after Sirolimus therapy, had been introduced and tacrolimus doses reduced, the median fell to 0.6 mg/dL. The nephrotic nephritic syndrome in 2 cases resolved with a reduction in tacrolimus therapy. Of 11 patients showing improvement in renal function on sirolimus, 4 patients have continued on sirolimus. One From the Pediatric GI (S.H., C.T.), Pharmacy (D.C.), and Surgery (K.I., D.S., B.S., A.L.), University of Nebraska Medical Center, Omaha, Nebraska, USA. Address reprint requests to Dr S. Horslen, Department of Pediatric GI, University of Nebraska Medical Center, Omaha, NE 68198. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 934 –935 (2002)
PEDIATRIC INTESTINAL TX
patient’s renal dysfunction resolved, which permitted discontinuation of sirolimus. Two patients lost their intestinal graft while on the drug, one of whom was the child originally started on it for recurrent rejection. In the first 18 months of sirolimus treatment, she had only one mild episode of rejection; however, just over 18 months after starting the drug she developed moderate rejection, which progressed to severe rejection and led to explantation of her graft. Overall, this child underwent 14 or 15 episodes of acute rejection during the 5 years that the graft was in place in spite of significant levels of immunosuppression throughout. The second lost graft followed a dehydrating diarrheal illness. The graft was presumably lost to ischemic injury, but there was some evidence of mesenteric arteriopathy suggestive of chronic vascular rejection of the intestinal graft. Finally, 4 patients, despite improvements in their renal function, have died—3 due to septic complications and 1 following a ruptured aneurysm of the donor aorta. One final patient who was started on sirolimus after an episode of acute rejection followed by persistent diarrhea showed no improvement in stool output, although repeat biopsies showed no evidence of further acute rejection. In all 16 patients (follow-up of between 10 days and 19 months), only a single episode of acute rejection occurred, which took place in the child who started sirolimus for
935
recurrent rejection and ultimately lost her graft to rejection. A considerable number of complications have been encountered, including neutropenia in 4 cases, fever of unknown origin in 2 cases, hypertriglyceridemia in 9 cases, 1 episode of poor wound healing, 1 of ruptured aortic graft aneurysm, 1 of multiple chalazia (meibomian cysts), and 1 of scrotal (Fournier) gangrene. DISCUSSION
In conclusion, sirolimus appears to be a powerful immunosuppressant that can effectively prevent most episodes of acute cellular rejection and appears to have benefits in renal function; however, in our experience has been associated with a high incidence of complications, some of which are quite unusual, such as the scrotal gangrene, multiple chalazia, and aortic aneurysm. Clearly, additional studies are required to verify the indications for use of sirolimus to identify the ideal blood levels for optimal safety and efficacy, and also to determine whether the safety profile of this drug justifies its use in childhood. It is not clear whether the high incidence of complications in our group is related solely to the fact that sirolimus was introduced as a rescue therapy only to children who already had a substantially higher risk of sepsis and other complications.
Initial Experience Using Rapamycin Immunosuppression in Pediatric Intestinal Transplant Recipients S. Horslen, C. Torres, D. Collier, K. Iyer, D. Sudan, B. Shaw, and A. Langas
R
APAMYCIN is a macrocyclic lactone immunosuppressant that is substantially free from nephrotoxic side effects. We present our preliminary experience with the use of rapamycin (sirolimus) in children following intestinal transplantation. Standard immunosuppression for small bowel transplantation at our center is a combination of tacrolimus and steroids. Renal dysfunction is the most frequent drug-related problem with standard tacrolimusbased immunosuppression. In the immediate postoperative period, tacrolimus levels are maintained in the 20- to 25-ng/mL range. RESULTS AND METHODS Sirolimus was introduced in 16 pediatric intestinal transplant patients (8 females, age range 1.3 to 19 years) in an attempt to spare the effects of calcineurin inhibitors on renal function. Twelve patients underwent combined liver and bowel transplantation, and four had isolated intestinal transplantation. Sirolimus was introduced between 13 days and 4.5 years after transplantation. The initial loading dose of sirolimus was 2 to 3 mg/m2 followed by 1 mg/m2 once per day and adjusted to achieve blood levels in the 8to 10-ng/mL range. Some of the children required sirolimus twice daily to achieve these levels, which differs from the adult data, which suggests that a once-daily dose is sufficient. As a general rule, the tacrolimus dose was decreased by 50% and adjusted according to blood levels, depending on the individual patient’s immunosuppressive requirements. The indications for the introduction of sirolimus therapy were nephrotoxicity in 14 patients, 1 for recurrent rejection, and 1 for acute rejection followed by persistent diarrhea. The child who received the drug for recurrent rejection also developed nephropathy in the form of nephrotic nephritic syndrome some months later, and this was believed to be related to the continued high levels of tacrolimus. Nephropathy in the other 14 patients was 0041-1345/02/$–see front matter PII S0041-1345(02)02677-5 934
manifested by hypertension and elevated creatinine in 12 patients. Two patients had evidence of pretransplant renal dysfunction. Two additional patients developed nephrotic nephritic syndrome, one of whom had evidence of pretransplant renal dysfunction. All 3 patients with nephritis underwent renal biopsy. The histology showed focal segmental glomerular sclerosis and thrombotic microangiopathy.
RESULTS
Of the 15 patients who had evidence of nephrotoxicity, 11 improved; 2 developed neutropenia immediately after starting on sirolimus, forcing its discontinuation before an effect could be seen; and 2 patients did not improve. Of the 2 not improving, one went on to receive a kidney transplant (this child had preexisting renal dysfunction and developed glomerular sclerosis), and the other patient died of early septic complications. Improvement in renal function was documented by better control of hypertension and reduced creatinine levels. Median creatinine level for this group before sirolimus therapy was 1.5 mg/dL and, after Sirolimus therapy, had been introduced and tacrolimus doses reduced, the median fell to 0.6 mg/dL. The nephrotic nephritic syndrome in 2 cases resolved with a reduction in tacrolimus therapy. Of 11 patients showing improvement in renal function on sirolimus, 4 patients have continued on sirolimus. One From the Pediatric GI (S.H., C.T.), Pharmacy (D.C.), and Surgery (K.I., D.S., B.S., A.L.), University of Nebraska Medical Center, Omaha, Nebraska, USA. Address reprint requests to Dr S. Horslen, Department of Pediatric GI, University of Nebraska Medical Center, Omaha, NE 68198. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 934 –935 (2002)
PEDIATRIC INTESTINAL TX
patient’s renal dysfunction resolved, which permitted discontinuation of sirolimus. Two patients lost their intestinal graft while on the drug, one of whom was the child originally started on it for recurrent rejection. In the first 18 months of sirolimus treatment, she had only one mild episode of rejection; however, just over 18 months after starting the drug she developed moderate rejection, which progressed to severe rejection and led to explantation of her graft. Overall, this child underwent 14 or 15 episodes of acute rejection during the 5 years that the graft was in place in spite of significant levels of immunosuppression throughout. The second lost graft followed a dehydrating diarrheal illness. The graft was presumably lost to ischemic injury, but there was some evidence of mesenteric arteriopathy suggestive of chronic vascular rejection of the intestinal graft. Finally, 4 patients, despite improvements in their renal function, have died—3 due to septic complications and 1 following a ruptured aneurysm of the donor aorta. One final patient who was started on sirolimus after an episode of acute rejection followed by persistent diarrhea showed no improvement in stool output, although repeat biopsies showed no evidence of further acute rejection. In all 16 patients (follow-up of between 10 days and 19 months), only a single episode of acute rejection occurred, which took place in the child who started sirolimus for
935
recurrent rejection and ultimately lost her graft to rejection. A considerable number of complications have been encountered, including neutropenia in 4 cases, fever of unknown origin in 2 cases, hypertriglyceridemia in 9 cases, 1 episode of poor wound healing, 1 of ruptured aortic graft aneurysm, 1 of multiple chalazia (meibomian cysts), and 1 of scrotal (Fournier) gangrene. DISCUSSION
In conclusion, sirolimus appears to be a powerful immunosuppressant that can effectively prevent most episodes of acute cellular rejection and appears to have benefits in renal function; however, in our experience has been associated with a high incidence of complications, some of which are quite unusual, such as the scrotal gangrene, multiple chalazia, and aortic aneurysm. Clearly, additional studies are required to verify the indications for use of sirolimus to identify the ideal blood levels for optimal safety and efficacy, and also to determine whether the safety profile of this drug justifies its use in childhood. It is not clear whether the high incidence of complications in our group is related solely to the fact that sirolimus was introduced as a rescue therapy only to children who already had a substantially higher risk of sepsis and other complications.