The absence of chronic rejection in pediatric primary liver transplant patients who are maintained on tacrolimus-based immunosuppression: a long-term analysis.

BACKGROUND: Although the outcome of liver transplantation has improved significantly during the past two decades, graft loss caused by chronic rejection after liver transplantation still occurs in 2% to 20% of recipients. The overall incidence of chronic rejection is also reported to be low in adult recipients, and risk factors have been identified. Chronic rejection is associated with the inability to maintain baseline immunosuppression. Additionally, the diagnoses of primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, hepatitis B virus, and hepatitis C virus, common indications for liver transplantation in adults, are associated with a higher incidence of chronic rejection. Fortunately, these diagnoses are rarely seen in children. Little is known about chronic rejection in long-term pediatric liver transplant survivors. The purpose of this longitudinal study was to examine the incidence of biopsy-proven chronic rejection in long-term survivors of primary pediatric liver transplantation under tacrolimus-based immunosuppression. METHODS: From October 1989 to December 1992, 166 children (boys=95, girls=71; mean age=5.0+/-2.9 years) received a primary liver transplant. These patients were followed until March 2000 with a mean follow-up of 9+/-0.8 (range, 7.4-10.4) years. All liver biopsy specimens and explanted grafts were evaluated for evidence of chronic rejection using the International Banff Criteria. RESULTS: The mortality rate during the follow-up period was 15% (n=25). Retransplantation was required in 11% (n=18) of recipients. Actuarial patient and graft survival rates at 10 years were 84.9% and 80.1%, respectively. There were 535 liver biopsy samples available for evaluation, including the 18 explanted allografts. Biopsy specimens of three other functioning allografts showed evidence of chronic rejection. Immunosuppression had been discontinued or drastically reduced in these recipients because of life-threatening infections, noncompliance, or both. On restoring baseline immunosuppression, all three children had normalized liver function and the allografts were maintained; the liver transplant patients who are alive currently have normal liver functions. CONCLUSION: The findings of this study suggest that chronic rejection does not occur in pediatric liver transplant recipients receiving tacrolimus-based immunosuppression, provided baseline immunosuppression is maintained.

Pediatric intestinal transplantation: the resected allograft.

We reviewed the clinical and pathologic finding of 22 resected allografts from 19 of the 83 children who underwent a variety of small intestinal transplant procedures in the years 1990-2000 at the Children's Hospital of Pittsburgh. Resections were compared with prior mucosal biopsies because resections allow for evaluation of the entire bowel thickness, including the feeding vessels, and obviate the problems of limited sampling. Partial resections that were done soon after the transplant, or soon after additional surgery, were for surgical problems such as leaks, adhesions, and volvulus. None had biopsy features suggestive of rejection or infection. Partial resections done late (6 months or more) after transplantation were more likely to be related to allograft immune biology; two had a sclerosing peritonitis that was confined to the allograft, and one had an obstructing carcinoma arising in the allograft mucosa. One patient had a localized stricture, demonstrated to be due to graft vascular disease at partial resection, and this patient went on to have the allograft removed a year later for chronic rejection. Early complete allograft enterectomies were for refractory acute cellular rejection, 1-2 months following transplant. One was removed for pancreatitis and liver failure from operative complications. Late allograft enterectomies were generally for chronic rejection, some with residual acute rejection, but there were also a number of patients who had multiple superimposed conditions such as cytomegalovirus, Epstein-Barr virus, and post-transplant lymphoproliferative disorder in various combinations. One had idiopathic scarring and developed an adynamic bowel that remains unexplained. Examination of the resected specimens allows for dissection of the multiple contributions to graft failure, especially the vascular disease that can rarely be seen on mucosal biopsy. An unexpected finding was the impressive hypertrophy of neural elements, nerves, and ganglion cells in many of the patients, the significance of which requires further investigation.

Chronic rejection of small bowel grafts: pediatric and adult study of risk factors and morphologic progression.

One hundred and seventy-two patients underwent small bowel transplantation at Children's Hospital of Pittsburgh and University of Pittsburgh Medical Center between May 1990 and August 2001. Thirty-four patients had complete or partial resection of their primary graft and in 15, histologic features of chronic rejection were present in the resected small bowel. This is a descriptive and correlative study of the demographic, perioperative, and histologic features associated with progression to intestinal graft failure. Variable features associated with an increased risk of chronic rejection included acute rejection within the 1st month, increased number and higher grade of acute rejection episodes, isolated small bowel grafts rather than small bowel-liver grafts, older recipient age, non-Caucasian race, and Caucasian to non-Caucasian transplant. The mucosal biopsies showed predictive changes many months before the grafts were excised. The mucosal biopsy diagnosis of chronic vascular rejection can be difficult because the affected vessels, the distal branches of the mesenteric arteries, and the larger arteries of the subserosa and submucosa are not routinely sampled. The possibility of underlying arteriopathy, however, can be inferred in some instances from the presence of secondary mucosal changes in the small bowel biopsies though the "early" changes lack specificity. It is the progression of biopsy findings over time that is predictive of outcome. It is important to recognize the persistence of "late" mucosal changes of chronic rejection so that patients are not subjected to increased immune suppression when it is unlikely to be of significant benefit.

Steroid-resistant nephrotic syndrome and congenital anomalies of kidneys: evidence of locus on chromosome 13q.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) and congenital anomalies of kidney and urinary tract (CAKUT) are major causes of renal dysfunction in children. Although a few patients with 13q deletion have been previously reported with renal anomalies, the association of SRNS with 13q has not been reported and critical regions associated with CAKUT have not been identified. We present the results of deletion mapping studies to identify the critical regions. METHODS: Cytogenetic and deletion mapping studies were performed on DNA obtained from peripheral blood of two children with renal anomalies and interstitial deletion of 13q as well as their parents. Twenty eight microsatellite markers with a spacing of 1-8 Mb (1-3 cM) were utilized. RESULTS: The patients (both males, 5 and 10 years old) had varying severity of developmental delay and other neurologic disorders. The renal involvement included hydronephrosis, ureterocele, renal dysplasia, and mesangioproliferative SRNS. Our studies imply existence of at least two critical regions in the 13q area that are linked to CAKUT. The first is a 7 Mb region defined by markers D13S776 and D13S891 shared by both patients. The second is a much larger region extending at least 33 Mb above D13S776 seen in one patient with severe renal malformations and SRNS. CONCLUSION: We report an association of chromosome 13q with CAKUT as well as SRNS. Our studies suggest the presence of more than one gene in this region that is likely to be involved in renal development and function.