Evolutionary experience with immunosuppression in pediatric intestinal transplantation.
OBJECTIVE
Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes.


METHODS
From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 +/- 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing.


RESULTS
The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation.


CONCLUSIONS
Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike.
Bond
Geoffrey J
GJ
Thomas E Starzl Transplantation Institute, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Mazariegos
George V
GV
Sindhi
Rakesh
R
Abu-Elmagd
Kareem M
KM
Reyes
Jorge
J
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use; D003586:Cytomegalovirus Infections / Q000209:etiology; D000077561:Daclizumab; D020031:Epstein-Barr Virus Infections / Q000209:etiology; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control / Q000628:therapy; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D007410:Intestinal Diseases / Q000601:surgery; D007422:Intestines / Q000637:transplantation*; D008297:Male; D016377:Organ Transplantation / Q000009:adverse effects; D016019:Survival Analysis; D016559:Tacrolimus / Q000627:therapeutic use; D019172:Transplantation Conditioning
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D000077561:Daclizumab; D016559:Tacrolimus